OMIM Entry - #219700 - CYSTIC FIBROSIS; CF

#219700 ICD+

ICD10CM: E84.9,
ICD10CM: E84,
ICD9CM: 277.0,
SNOMEDCT: 190905008

ICD10CM: E84.9, ICD10CM: E84, ICD9CM: 277.0, SNOMEDCT: 190905008

CYSTIC FIBROSIS; CF

Alternative titles; symbols

MUCOVISCIDOSIS

Phenotype Gene Relationships

Location	Phenotype	Phenotype MIM number	Gene/Locus	Gene/Locus MIM number
7q31.2	Cystic fibrosis	219700	CFTR	602421
19q13.2	{Cystic fibrosis lung disease, modifier of}	219700	TGFB1	190180

Clinical Synopsis

TEXT

A number sign (#) is used with this entry because the disorder is caused by mutations in the cystic fibrosis conductance regulator gene (CFTR; 602421), located on chromosome 7.

Description

Formerly known as cystic fibrosis of the pancreas, this entity has increasingly been labeled simply 'cystic fibrosis.' Manifestations relate not only to the disruption of exocrine function of the pancreas but also to intestinal glands (meconium ileus), biliary tree (biliary cirrhosis), bronchial glands (chronic bronchopulmonary infection with emphysema), and sweat glands (high sweat electrolyte with depletion in a hot environment). Infertility occurs in males and females.

For discussion of a phenotype consisting of bronchiectasis with or without elevated sweat chloride caused by mutation in the genes encoding the 3 subunits of the epithelial sodium channel, see BESC1 (211400).

Clinical Features

The mildest extreme of CF is represented by patients not diagnosed until middle age (Scully et al., 1977). The phenotypic variability in CF was analyzed by Sing et al. (1982). In an inbred kindred in North Carolina, a mild form of cystic fibrosis was described by Knowles et al. (1989). There was 1 instance of mother-daughter involvement, the mother being related to her husband. One of the presumed homozygotes was a 62-year-old woman. Another was her 52-year-old sister, the mother of the affected proposita. The daughter was an intensive care nurse, the mother of a normal daughter. Manifestations in the family were predominantly pulmonary; pancreatic exocrine insufficiency was not a conspicuous feature, especially in the older patients.

The 2 subgroups defined by the A and C haplotypes of polymorphisms closely linked to the CF locus on chromosome 7, reported by Estivill et al. (1987), have clinical differences in terms of the frequency of meconium ileus, pseudomonas infections, and pancreatic disease (Woo, 1988).

Gasparini et al. (1990) described a RFLP DNA marker closely linked to the CF locus which showed an allelic correlation with severity of the disorder: the genotype 2/2 was associated with severe disease; the genotype 1/2 was overrepresented in patients with very mild clinical manifestations, including pancreatic insufficiency, absence of meconium ileus, and absence of Pseudomonas colonization.

Meconium Ileus

Allan et al. (1981) showed that sibs tend to show recurrence of meconium ileus as a feature of cystic fibrosis. The distal intestinal obstruction syndrome is a 'meconium ileus equivalent' that occurs in adolescents and adults with CF. It is the consequence of the abnormally viscid mucofeculant material in the terminal ileum and right colon, where the fecal stream is normally liquid.Typical features are recurrent episodes of RLQ pain with palpable mass in the right iliac fossa. Symptoms are exacerbated by eating.

Mornet et al. (1988) determined the haplotype associated with cystic fibrosis in 41 families using 4 DNA probes, all of which are tightly linked to the CF gene. In 17 of the families an affected child had meconium ileus, and in the other 24 families there was a child without meconium ileus. A different haplotype was associated with the 2 types of families, suggesting that multiple allelism, i.e., different mutations at the same locus, accounts for CF with or without meconium ileus.

Liver Disease

Gaskin et al. (1988) found that 96% of patients with cystic fibrosis and evidence of liver disease had biliary tract obstruction, usually a stricture of the distal common bile duct. All patients without liver disease had normal intrahepatic and common-duct excretion of tracer.

Bilton et al. (1990) described a case of cystic fibrosis complicated by common bile duct stenosis.

Gabolde et al. (2001) showed that the presence of cirrhosis in patients with cystic fibrosis is significantly associated with either homozygous or compound heterozygous mutations in the MBL2 gene (154545), which encodes mannose-binding lectin (MBL). The authors compared 216 patients homozygous for the delta-F508 mutation (602421.0001) and found that 5.4% of those homozygous or compound heterozygous for wildtype mannose-binding lectin had cirrhosis, while 30.8% of those homozygous or compound heterozygous for mutant alleles had cirrhosis (p = 0.008).

Approximately 3 to 5% of patients with cystic fibrosis develop severe liver disease defined as cirrhosis with portal hypertension. Bartlett et al. (2009) performed a 2-stage case control study enrolling patients with CF and severe liver disease with portal hypertension from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America. In the first stage, 124 patients with CF and severe liver disease, enrolled between January 1999 and December 2004, and 843 control patients without CF-related liver disease (all assessed at greater than 15 years of age) were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the 2 genes that were positive from the first stage were tested in an additional 136 patients with CF-related liver disease, enrolled between January 2005 and February 2007, and in 1,088 with no CF-related liver disease. The combined analysis of the initial and replication studies by logistic regression showed CF-related liver disease to be associated with the SERPINA1 Z allele (107400.0011) (odds ratio = 5.04; 95% confidence interval, 2.88-8.83; p = 1.5 x 10(-8)). Bartlett et al. (2009) concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients carrying the Z allele are at greater risk (odds ratio = approximately 5) of developing severe liver disease with portal hypertension.

Pancreatic Insufficiency

Approximately 15% of CF patients do not have pancreatic insufficiency, i.e., are 'pancreatic sufficient.' Kerem et al. (1989) performed linkage disequilibrium and haplotype association studies of patients in 2 clinical subgroups, one pancreatic insufficient (PI) and the other pancreatic sufficient (PS). Significant differences were found in allelic and haplotype distributions in the 2 groups. The data suggested that most of the CF-PI patients were descendants of a single mutational event at the CF locus, whereas the CF-PS patients resulted from multiple, different mutations. Corey et al. (1989) commented on the intrafamilial concordance for pancreatic insufficiency in CF.

Devoto et al. (1989) studied the allele and haplotype frequencies of 5 polymorphic DNA markers near the CF locus in 355 CF patients from Belgium, the German Democratic Republic, Greece, and Italy who were divided into 2 groups according to whether or not they were taking supplementary pancreatic enzymes. The distributions of alleles and haplotypes revealed by 2 of the probes were always different in patients with or without pancreatic insufficiency in all the populations studied. In the case of 1 haplotype that was present in 73% of all the CF chromosomes in their sample, they found homozygosity in only 28% of patients without pancreatic insufficiency as contrasted with 64% who were homozygous and had pancreatic insufficiency. Like other workers, they concluded that this indicated that pancreatic insufficiency and sufficiency are associated with different mutations at the CF locus.

Ferrari et al. (1990) studied the distribution of haplotypes based on 8 polymorphic DNA markers linked to CF in 163 Italian patients and correlated the findings with clinical presentation. Among 19 pancreatic sufficient patients, 6 (31.6%) showed at least 1 copy of a rare phenotype which was present in only 16 of 138 patients (11.6%) with pancreatic insufficiency. In addition, only 5 pancreatic sufficient patients were homozygous for the common 2,1 haplotype as compared with 88 patients (63.8%) with pancreatic insufficiency. Kristidis et al. (1992) likewise found intrafamilial consistency of the pancreatic phenotype, whether pancreatic sufficient or insufficient. Furthermore, the PS phenotype occurred in patients who had 1 or 2 mild CFTR mutations, such as arg117-to-his (602421.0005), arg334-to-trp (602421.0034), arg347-to-pro (602421.0006), ala455-to-glu (602421.0007), and pro574-to-his (602421.0018), whereas the PI phenotype occurred in patients with 2 severe alleles, such as phe508-to-del (602421.0001), ile507-to-del (602421.0002), gln493-to-ter (602421.0003), gly542-to-ter (602421.0009), arg553-to-ter (602421.0014), and trp1282-to-ter (602421.0022).

Borgo et al. (1993) commented on the phenotypic intrafamilial heterogeneity displayed by an Italian family in which 3 sibs, 2 of whom were dizygotic twins, were compound heterozygotes for the delF508 (602421.0001) and the 1717,-1,G-A splicing mutation (602421.0008). While close intrafamilial concordance was found for exocrine pancreatic phenotype, the pulmonary phenotype varied widely. They suggested that interaction of the CFTR protein with tissue-specific proteins or the action of modifier loci (which may be operationally identical possibilities) plays a role in intrafamilial variability.

Barreto et al. (1991) concluded that the father of a girl with severe CF also had CF but was mildly affected. The child was homozygous for the delta-F508 mutation associated with haplotype B; the father was a compound heterozygote for this mutation and a second CF mutation associated with haplotype C. Perhaps it should not be surprising that some patients with cystic fibrosis have no pancreatic lesions (Oppenheimer, 1972).

Sharer et al. (1998) and Cohn et al. (1998) demonstrated that heterozygosity for CFTR mutations can lead to 'idiopathic' chronic pancreatitis, especially when the mutation is associated with the 5T allele of the variable number of thymidines in intron 8 of the CFTR gene.

Pulmonary Disease

Pier et al. (1996) provided an experimental explanation for the susceptibility of CF patients to chronic Pseudomonas aeruginosa lung infections. They found that cultured human airway epithelial cells expressing the delta-F508 allele of the CFTR gene were defective in uptake of P. aeruginosa compared with cells expressing the wildtype allele. P. aeruginosa lipopolysaccharide-core oligosaccharide was identified as the bacterial ligand for epithelial cell ingestion; exogenous oligosaccharide inhibited bacterial ingestion in a neonatal mouse model, resulting in increased amounts of bacteria in the lungs. The authors concluded that CFTR may normally contribute to a host-defense mechanism that is important for clearance of P. aeruginosa from the respiratory tract.

Ernst et al. (1999) identified unique lipopolysaccharide structures synthesized by P. aeruginosa within CF patient airways. P. aeruginosa synthesized lipopolysaccharide with specific lipid A structures, indicating unique recognition of the CF airway environment. CF-specific lipid A forms containing palmitate and aminoarabinose were associated with resistance to cationic antimicrobial peptides and increased inflammatory responses, indicating that they are likely to be involved in airway disease.

Because mannose-binding lectin (MBL), encoded by the MBL2 gene (154545), is a key factor in innate immunity, and lung infections are a leading cause of morbidity and mortality in CF, Garred et al. (1999) investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, Garred et al. (1999) estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes.

Davies et al. (2000) found that MBL binds to Burkholderia cepacia, an important pathogen in patients with CF, and leads to complement activation, but that this was not the case for Pseudomonas aeruginosa, the more common colonizing organism in CF. Davies et al. (2000) suggested that patients with CF and mannose-binding lectin deficiency would be at a particularly high risk of B. cepacia colonization. The lack of binding to P. aeruginosa suggests that the effect of this organism on lung function in patients with MBL-deficient CF reflects a role for MBL, either in intercurrent infections with other organisms, or in the inflammatory process.

In an association study involving 112 patients with cystic fibrosis, Yarden et al. (2004) found that patients with the MBL2 A/O or O/O genotypes were more likely to have a more severe pulmonary phenotype than patients with the A/A genotype (p = 0.002). No association was found between the MBL2 genotype and the age at first infection with P. aeruginosa. Yarden et al. (2004) concluded that it is very likely that MBL2 is a modulating factor in cystic fibrosis.

Tarran et al. (2001) stated that there is controversy over whether abnormalities in the salt concentration or volume of airway surface liquid (ASL) initiate CF airway disease. Using CF mouse nasal epithelia, they showed that an increase in goblet cell number was associated with decreased ASL volume rather than abnormal Cl- concentration. Aerosolization of osmolytes in vivo failed to raise ASL volume. Osmolytes and pharmacologic agents were effective in producing isotonic volume responses in human airway epithelia but were typically short acting and less effective in CF cultures with prolonged volume hyperabsorption and mucus accumulation. These data showed that therapies can be designed to normalize ASL volume without producing deleterious compositional changes in ASL, and that therapeutic efficacy will likely depend on development of long-acting pharmacologic agents and/or an increased efficiency of osmolyte delivery.

In 69 Italian patients with CF due to homozygosity for the delF508 mutation in the CFTR gene (F508del; 602421.0001), De Rose et al. (2005) found that those who also carried the R131 allele of the immunoglobulin Fc-gamma receptor II gene (FCGR2A; see 146790.0001) had a 4-fold increased risk of acquiring chronic Pseudomonas aeruginosa infection (p = 0.042). De Rose et al. (2005) suggested that FCGR2A locus variability contributes to this infection susceptibility in CF patients.

Infertility

Oppenheimer et al. (1970) suggested that characteristics of cervical mucus may account for infertility in females with cystic fibrosis. Congenital bilateral absence of the vas deferens (CBAVD; 277180) is a usual cause of male infertility in cystic fibrosis. It also occurs with CFTR mutations in heterozygous state, especially when associated with the polymorphic number of thymidines in intron 8, specifically the 5T allele.

Carcinoma

Siraganian et al. (1987) pointed to adenocarcinoma of the ileum in 3 males with cystic fibrosis. The diagnosis was made between ages 29 and 34 years.

From a pancreatic adenocarcinoma developing in a 26-year-old patient with cystic fibrosis due to the phenylalanine-508 deletion, Schoumacher et al. (1990) established a cell line in which the cells showed morphologic and chemical characteristics typical of pancreatic duct cells and showed physiologic properties of CF cells. Schoumacher et al. (1990) suggested that the cell line, which had been stable through more than 80 passages over a 2-year period, could serve as a continuous cell line for studies of the CF defect. Bradbury et al. (1992) demonstrated that the CFTR protein is involved in cAMP-dependent regulation of endocytosis and exocytosis. In a study of pancreatic cancer cells derived from a CF patient, they found that plasma membrane recycling did not occur until normal CFTR was provided.

Neglia et al. (1995) performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from population-based data on the incidence of cancer. They also analyzed proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. The final results indicated that although the overall risk of cancer in patients with cystic fibrosis is similar to that of the general population, there is an increased risk of digestive tract cancers. They recommended that persistent or unexplained gastrointestinal symptoms in CF patients should be carefully investigated.

Patients with cystic fibrosis have altered levels of plasma fatty acids. Affected tissues from cystic fibrosis knockout mice show elevated levels of arachidonic acid and decreased levels of docosahexaenoic acid. Freedman et al. (2004) performed studies of fatty acids in nasal and rectal biopsy specimens, nasal epithelial scrapings, and plasma from 38 patients with cystic fibrosis, and found alterations in fatty acids similar to those in the knockout mice.

Other Features

Delayed puberty is common among individuals with cystic fibrosis and is usually attributed to chronic disease and/or poor nutrition. However, delayed puberty has been reported as a feature of CF even in the setting of good nutritional and clinical status (Johannesson et al., 1997).

Inheritance

Recessive inheritance of cystic fibrosis was first shown clearly by Lowe et al. (1949). Roberts (1960) collected family data which appeared to him inconsistent with the quarter ratio expected of a recessive trait. Bulmer (1961) pointed out, however, that when proper correction is made for ascertainment bias, the observed proportions may agree with those expected for a recessive trait.

Rather than estimating the frequency of the CF gene from the square root of the incidence figure, Danks et al. (1983) used the frequency of CF in first cousins. The estimate of gene frequency was 0.0281 as contrasted with 0.0198 (based on direct count). Danks et al. (1983) suggested that the disparity between the 2 estimates might be the existence of 2 gene loci, each with a frequency of 0.0140 for the CF gene and a heterozygote frequency of 1 in 36. Thus, in Victoria, Australia, 1 in 18 persons might be heterozygous at one or the other locus. Later, however, the authors published a retraction and concluded that they had no evidence of more than 1 locus.

For risk analysis in cystic fibrosis, Edwards and Miciak (1990) proposed a simple procedure called the 'slash sheet.' They pointed out that the various methods of estimating genetic risk fall into 2 main groups: first, enumerating all possibilities and excluding those inconsistent with the tests, a simple procedure in small families, and second, using conditional arguments. The latter approach uses Bayes theorem. The former approach, Edwards and Miciak (1990) pointed out, follows a procedure advanced in 1654 by Pascal, following correspondence with Fermat, on the problem of the Chevalier de Mere, now known as the 'problem of points.' Two noblemen were gambling, and, while one was winning, the other was called away and the game was abandoned. How should the stakes be divided? Edwards and Miciak (1990) noted that 'genetic risk is merely an unfinished game of chance.'

See Hodge et al. (1999) for a discussion of calculation of CF risk in a fetus with 1 identified mutation in CFTR and echogenic bowel.

Cytogenetics

Park et al. (1987) concluded that CF is distal to and on the 5-prime side of MET. They determined this by in situ hybridization on metaphase and prometaphase chromosomes of normal lymphocytes as well as lymphoblastoid cells containing a t(5;7)(q35;q22). Normal cells showed clustering of MET grains to 7q31. Furthermore, in the lymphoblastoid cell line, there was significant labeling within the 5q+ chromosome, confirming that MET is located distal to 7q22 with most grains clustered at 7q31. Somatic cell hybrids containing the derivative 7 showed on Southern analysis that the 3-prime portion of the MET gene, but not the 5-prime portion, was located there; thus, MET is at the translocation breakpoint. Studies in another cell line with a 7q32 translocation breakpoint indicated that MET is located at or proximal to 7q32. A break at this site was accompanied by loss of 3 markers within 1 cM of CF, suggesting that if MET is at the breakpoint on 7q31, CF is located distally.

In the course of studying a case of cystic fibrosis, Spence et al. (1988) discovered what appeared to be a case of uniparental disomy: the father did not contribute alleles to the propositus for markers near the CF locus or for centromeric markers on chromosome 7. High-resolution cytogenetic analysis was normal, and the result could not be explained by nonpaternity or a submicroscopic deletion. Uniparental disomy could be explained by various mechanisms such as monosomic conception with subsequent chromosome gain, trisomic conception followed by chromosome loss, postfertilization error, or gamete complementation. Patients with more than one genetic disorder might be suspected of having isodisomy, which should also be suspected in cases of an apparent new mutation leading to a recessive disorder when only 1 parent is heterozygous, and in cases of females affected with X-linked recessive disorders. Engel (1980) appears to have originated the concept of uniparental disomy and resulting isodisomy. Voss et al. (1988, 1989) also demonstrated uniparental disomy for chromosome 7 in a patient with cystic fibrosis.

Mapping

Mayo et al. (1980) attempted to map the cystic fibrosis gene by study of CF x mouse cell hybrids and examination for production of the cystic fibrosis mucociliary inhibitor. The strongest chance of assignment was for chromosome 4. Scambler et al. (1985) found that the albumin locus labeled by a DNA clone did not segregate with CF or with any of 6 other chromosome 4 markers. They estimated that about half the length of chromosome 4 was accounted for by the markers used. Eiberg et al. (1984) found a hint of linkage to F13B (134580); the maximum lod score was 1.71 at a recombination fraction of 0.05 for males and females combined. Linkage with 56 other genetic markers was negative (Eiberg et al., 1984). Eiberg et al. (1985) showed that cystic fibrosis and paraoxonase (PON; 168820) are linked; the maximum lod score was 3.70 at theta = 0.07 in males and 0.00 in females.

Tsui et al. (1985) found that the CF locus is linked to that of a DNA marker which is also linked to the PON locus, which in turn by independent evidence is linked to CF, thus closing the circle. The DNA marker was provisionally called D0CRI-917. The interval between the marker and PON was about 5 cM and the interval between it and CF about 15 cM. Whether the order is marker--PON--CF or PON--marker--CF was not certain; the former order was favored by 9:5 odds. Knowlton et al. (1985) reported that the anonymous probe D0CRI-917, linked to CF with about 15% recombination, is located on chromosome 7. White et al. (1985) showed very tight linkage to the MET oncogene (164860), which was assigned to the midportion of 7q. Wainwright et al. (1985) reported tight linkage also to the gene for another anonymous DNA probe, pJ3.11, which was assigned to 7cen-7q22. The closely linked probes pJ3.11 and MET are sufficiently informative to permit carrier detection in 80% of families in which there is a living CF child and unaffected sibs (Farrall et al., 1986). Scambler et al. (1985) showed that the COL1A2 gene (120160) is linked to CF (maximum lod for the sexes combined = 3.27 at a male recombination fraction of 0.08 and a female recombination fraction of 0.15.) PON and CF show recombination frequency of about 10%. CF is about 10 cM from both TCRB (186930) and COL1A2. TCRB and COL1A2 are not closely linked; thus, CF lies between them in the proximal part of 7q22. Wainwright et al. (1986) presented linkage data for COL1A2 versus CF (lod = 3.58 at theta = 0.10), TCRB versus CF (lod = 2.20 at theta = 0.15) and TCRB versus PON (all lods negative). Based on combined linkage data from 50 informative 2-generation families, Buchwald et al. (1986) concluded that CF is 19 cM from COL1A2, which is located at 7q21.3-q22.1. COL1A2 is closely linked to D7S15 and to PON. The probable order is COL1A2--D7S15--PON--CF. The regional localization of CF is 7q22.3-q23.1. Linkage of cystic fibrosis to various DNA markers and/or classical markers was reported in a series of articles by Beaudet et al. (1986), White et al. (1986), Bowcock et al. (1986), Farrall et al. (1986), Tsui et al. (1986), Spence et al. (1986), and Watkins et al. (1986). In Amish/Mennonite/Hutterite kindreds, Klinger et al. (1986) and Watkins et al. (1986) found close linkage with markers on chromosome 7, consistent with locus homogeneity for the defect causing CF in the populations that had been examined to date.

Estivill et al. (1987) identified a candidate for the cystic fibrosis locus by using a 'rare-cutter cosmid library.' They found a genomic region with the characteristics of an HTF island in high linkage disequilibrium with CF. The fact that the sequence was conserved throughout mammalian evolution strengthens the view that this is the CF gene. HTF islands, standing for HpaII tiny fragments, have a sequence length of between 500 and 1000 bp and often include the first exons as well as upstream sequences 5-prime to coding genes (Bird, 1986; Brown and Bird, 1986). These HTF islands are regions of DNA rich in the nonmethylated dinucleotide CpG and contain clusters of sites for CpG-methylation-sensitive restriction enzymes. (There are about 30,000 HTF islands in the human genome.) Estivill et al. (1987) stated that 94% of the chromosomes are of haplotype B, which is present in only 34% of the chromosomes in the general population. In 127 Italian families, Estivill et al. (1988) studied linkage disequilibrium of markers at the locus containing the CpG-enriched methylation-free island designated D7S23. In a search for deletions by means of field inversion gel electrophoresis (FIGE), Morreau et al. (1988) analyzed DNA from 10 cystic fibrosis patients representing 19 different CF chromosomes. No differences were detected after digestion of the samples with 2 different restriction enzymes and hybridization with 4 different probes. The authors estimated that the percentage of deletions occurring within the CF region is less than 15.2% (95% confidence interval, N = 19). The fact that no patient with a combination of cystic fibrosis and a genetic syndrome due to a second affected locus in close vicinity to the CF locus has been described suggests that deletions are rare. Beaudet et al. (1989) found strong linkage disequilibrium between the CF locus and closely linked markers on chromosome 7. By in situ hybridization Duncan et al. (1988) mapped 2 DNA sequences closely linked to the CF locus to 7q31.3-q32. This is a more distal location than had been inferred from previous data.

Using cystic fibrosis and published CF haplotypes as the test bed, Collins and Morton (1998) illustrated how allelic association can be efficiently combined with linkage evidence to identify a region for positional cloning of a disease gene.

Molecular Genetics

For an extensive discussion of the molecular genetics of cystic fibrosis and a listing of allelic variants of the CFTR gene, see 602421.

Collins (1992) gave an update concerning the molecular biology of CF and the therapeutic implications thereof.

O'Sullivan and Freedman (2009) reviewed the clinical features, pathogenesis, diagnosis, molecular genetics, and current state of gene therapy in CF.

Heterogeneity

Vitale et al. (1986) found close linkage of the CF gene and the MET locus in 12 unrelated Italian cystic fibrosis families, thus supporting their hypothesis of genetic homogeneity based on the analysis of consanguineous marriages among 624 couples of CF parents. Lander and Botstein (1986) and Romeo et al. (1986) discussed further the consanguinity method for studying heterogeneity in cystic fibrosis. Estivill et al. (1987) used their haplotype data to argue against genetic heterogeneity at the CF locus. They proposed that the great majority of CF mutations found in the population arose from an original mutational event which occurred in the Caucasian population after racial divergence in man.

Nonclassic forms of CF have been associated with mutations that reduce but do not eliminate the function of the CFTR protein. Mekus et al. (1998) described a patient with a nonclassic CF phenotype in whom no CFTR mutations could be found. Groman et al. (2002) assessed whether alteration in CFTR function is responsible for the entire spectrum of nonclassic CF phenotypes. Extensive genetic analysis of the CFTR gene was performed in 74 patients with nonclassic CF. Furthermore, they evaluated 2 families that each included a proband without identified CFTR mutations and a sib with nonclassic CF to determine whether there was linkage to the CFTR locus and to measure the extent of CFTR function in the sweat gland and nasal epithelium. Of the 74 patients studied, Groman et al. (2002) found that 29 had 2 mutations in the CFTR gene (i.e., were either homozygous or compound heterozygous at the CFTR locus), 15 had 1 mutation, and 30 had no mutations. A genotype of 2 mutations was more common among patients who had been referred after screening for a panel of common CF-causing mutations that had identified 1 mutation than among those who had been referred after screening had identified no such mutations. Comparison of clinical features and sweat chloride concentrations revealed no significant differences among patients with 2, 1, or no CFTR mutations. Haplotype analysis in the 2 families in which 2 sibs had nonclassic CF showed no evidence of linkage to CFTR. Although each of the affected sibs had elevated sweat chloride concentrations, measurements of cAMP-mediated ion and fluid transport in the sweat gland and nasal epithelium demonstrated the presence of functional CFTR. Groman et al. (2002) concluded that factors other than mutations in the CFTR gene can produce phenotypes clinically indistinguishable from nonclassic CF caused by CFTR dysfunction.

Because proteinase-antiproteinase imbalances are common in both CF and alpha-1-antitrypsin deficiency (613490), Meyer et al. (2002) investigated the hypothesis that the common AAT deficiency alleles PI Z (107400.0011) and PI S (107400.0013) contribute to pulmonary prognosis in CF. In 269 CF patients from southern Germany, they determined the serum concentrations of AAT (107400) and C-reactive protein (CRP; 123260) by nephelometry and screened for the common AAT deficiency alleles by PCR and restriction enzyme digest. The onset of chronic bacterial colonization by P. aeruginosa was correlated with the AAT phenotypes PI MM, PI MS, and PI MZ. Only 3 of 9 (33%) CF patients diagnosed with either PI MS or PI MZ had developed chronic P. aeruginosa lung infection earlier in their lives; the remaining 6 PI MS or PI MZ patients showed a later onset of chronic P. aeruginosa lung infection. The results suggested that PI MS and PI MZ are not associated with a worse pulmonary prognosis in CF.

Mekus et al. (2003) examined modifying factors in CF by studying 34 highly concordant and highly discordant delF508 homozygous sib pairs selected from a group of 114 pairs for extreme disease phenotypes by nutritional and pulmonary status. They were typed for SNPs and short tandem repeat polymorphisms (STRPs) in a 24-cM CFTR-spanning region. Allele frequencies differed significantly at D7S495, located within a 21-cM distance 3-prime of CFTR, comparing concordant mildly affected, concordant severely affected, and discordant sib pairs. A rare haplotype of 2 SNPs within the leptin gene promoter (LEP; 164160) was found exclusively among the concordant mildly affected pairs. All concordant sib pairs shared the paternal delF508 chromosome between CFTR and D7S495, while the cohort of discordant sib pairs inherited equal proportions of recombined and nonrecombined parental chromosomes. Mekus et al. (2003) concluded that disease manifestation in CF is modulated by loci in the partially imprinted region 3-prime of CFTR that determine stature, food intake, and energy homeostasis, such as the Silver-Russell syndrome (180860) candidate gene region and LEP.

There is great variability of pulmonary phenotype and survival in cystic fibrosis, even among patients who are homozygous for the most prevalent mutation, delF508 (602421.0001). Although environmental influences may modify clinical disease, there is probably additional genetic variation (i.e., modifier genes) that contribute to the expression of the final phenotype. Drumm et al. (2005) studied variants of 10 genes previously reported as modifiers in cystic fibrosis in 2 studies with different patient samples. They first tested 808 patients who were homozygous for the delF508 mutation and were classified as having either severe or mild lung disease. Significant allelic and genotypic associations with phenotype were seen only for TGFB1 (190180), the gene encoding transforming growth factor beta-1, particularly the -509 and codon 10 polymorphisms. The odds ratio was about 2.2 for the highest-risk TGFB1 genotype (codon 10 CC; 190180.0007) in association with the phenotype of severe lung disease. In the replication (second) study, Drumm et al. (2005) tested 498 patients, with various CFTR genotypes and a range of values for forced expiratory volume in 1 second (FEV1), for an association of the TGFB1 codon 10 CC genotype with low FEV1. This replication study confirmed the association of the TGFB1 codon 10 CC genotype with more severe lung disease.

Buranawuti et al. (2007) determined the genotype of 4 variants of 3 putative CF modifier genes (TNF-alpha-238; TNF-alpha-308, 191160.0004; TGF-beta-509; and MBL2 A/O) in 3 groups of CF patients: 101 children under 17 years of age, 115 adults, and 38 nonsurviving adults (21 deceased and 17 lung transplant after 17 years of age). Genotype frequencies among adults and children with CF differed for TNF-alpha-238 (G/G vs G/A, p = 0.022) and MBL2 (A/A vs O/O, p = 0.016), suggesting that MBL2 O/O is associated with reduced survival beyond 17 years of age, whereas TNF-alpha-238 G/A appears to be associated with an increased chance of surviving beyond 17 years of age. When adults with CF were compared to nonsurviving adults with CF, genotype frequencies of both genes differed (TNF-alpha 238 G/G vs G/A, p = 0.0015; MBL2 A/A vs O/O, p = 0.009); the hazard ratio for TNF-alpha-238 G/G versus G/A was 0.25 and for MLB2 O/O versus A/A or A/O was 2.5. Buranawuti et al. (2007) concluded that TNF-alpha-238 G/A and MBL2 O/O genotypes appear to be genetic modifiers of survival in patients with CF.

In a study of 1,019 Canadian pediatric CF patients, Dorfman et al. (2008) found a significant association between earlier age of first P. aeruginosa infection and MBL2 deficiency (onset at 4.4, 7.0, and 8.0 years for low, intermediate, and high MBL2 groups according to MBL2 genotype, respectively; p = 0.0003). This effect was amplified in patients with the high-producing genotypes of TGFB1, including variant C of codon 10. MBL2 deficiency was also associated with more rapid decline of pulmonary function, most significantly in those homozygous for the high-producing TGFB1 genotypes (p = 0.0002). However, although TGFB1 affected the modulation of age of onset by MBL2, there was no significant direct impact of TGFB1 codon 10 genotypes alone. The findings provided evidence for a gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGFB1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.

Using quantitative transmission disequilibrium testing of 472 CF patient/parent trios, Bremer et al. (2008) found significant transmission distortion of 2 TGFB1 SNPs, -509 (rs1800469) and codon 10 (rs1982073), when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. A 3-SNP haplotype (CTC) composed of the -509 SNP C allele, the codon 10 T allele, and a 3-prime SNP rs8179181 C allele was highly associated with increased lung function in patients grouped by CFTR genotype. Bremer et al. (2008) concluded that TGFB1 is a modifier of CF lung disease, with a beneficial effect of certain variants on the pulmonary phenotype.

To identify genetic modifiers of lung disease severity in cystic fibrosis, Gu et al. (2009) performed a genomewide single-nucleotide polymorphism scan in 1 cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 (603502) as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone deacetylase-dependent transcriptional coregulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-null mice showed blunted effector function, associated with decreased NF-kappa-B p65 (RELA; 164014) transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease--a phenotype primarily dependent on hematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. Gu et al. (2009) concluded that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.

Association with Epithelial Sodium Channel Subunits

Stanke et al. (2006) genotyped 37 delF508 homozygous sib pairs for markers on chromosome 12p13, encompassing the epithelial sodium channel (ENaC) subunit A (SCNN1A; 600228) and TNF-alpha receptor (TNFRSF1A; 191190) genes, and chromosome 16p12, encompassing the SCNN1B (600760) and SCNN1G (600761) genes, as potential CF disease modifiers. Transmission disequilibrium was observed at SCNN1G and association with CF phenotype intrapair discordance was observed at SCNN1B. Family-based and case-control analyses and sequencing uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Stanke et al. (2006) suggested that the SCNN1B, SCNN1G, and TNFRSF1A genes may be modulators of CF disease by affecting changes in airway surface liquids and host inflammatory responses.

Fajac et al. (2008) screened the SCNN1B gene in 55 patients with idiopathic bronchiectasis (see 211400) who had 1 or no mutations in the CFTR gene and identified heterozygosity for 3 missense mutations in the SCNN1B gene (see, e.g., 600760.0015) in 5 patients, 3 of whom also carried a heterozygous mutation in CFTR (602421.0001 and 602421.0086). Fajac et al. (2008) concluded that variants in SCNN1B may be deleterious for sodium channel function and lead to bronchiectasis, especially in patients who also carry a mutation in the CFTR gene.

Viel et al. (2008) analyzed the SCNN1B and SCNN1G genes in 56 adult patients with classic CF and discordance between their respiratory phenotype and CFTR genotype, including 38 patients with a severe genotype and an unexpectedly mild lung phenotype, and 18 patients with a mild genotype and severe lung phenotype. Three patients carried at least 1 missense mutation in SCNN1B or SCNN1G, but analysis of sodium channel function by nasal potential difference (PD) measurements did not support that the variants were functional. Viel et al. (2008) concluded that variation in SCNN1B and SCNN1G genes do not modulate disease severity in the majority of CF patients.

Azad et al. (2009) identified several rare SCNN1A polymorphisms with an increased incidence in patients with a cystic fibrosis-like phenotype and 1 or no CFTR mutations versus controls, including several patients with no CFTR mutation who were heterozygous for a hyperactive variant (W493R; 600228.0007). The authors hypothesized that given the CF-carrier (3.3%) and the W493R-carrier (3.1%) frequency in some populations, there ma be a polygenic mechanism of disease involving CFTR and SCNN1A in some patients.

Mutesa et al. (2009) analyzed the CFTR gene in 60 unrelated Rwandan children who had CF-like symptoms and identified heterozygosity for a CFTR mutation in 5 patients (none were homozygous). Sequencing of the ENaC subunits revealed heterozygous mutations in the SCNN1A and SCNN1B genes in 4 patients, respectively, whereas the remaining patient was heterozygous for a mutation in both SCNN1B and SCNN1G. Among the 55 patients who were negative for mutation in CFTR, only polymorphisms were found in the ENaC genes. Mutesa et al. (2009) concluded that some cases of CF-like syndrome in Africa may be associated with mutations in CFTR and ENaC genes.

Pathogenesis

Frizzell (1987) pointed out that cystic fibrosis is of interest to neuroscientists because it appears to be a disease of ion channels. It is apparently not the conduction properties of ion channels that are affected, but rather their gating by chemical agonists. These conductance pathways appear to be unique to epithelial cells in which salt and water transport rates are governed by cyclic AMP and calcium-dependent regulatory processes.

Decrease in fluid and salt secretion is responsible for the blockage of exocrine outflow from the pancreas and the accumulation of heavy dehydrated mucous in the airways. In sweat glands, salt reabsorption is defective. This is the basis of the folkloric anecdote that the midwife would lick the forehead of the newborn and, if the sweat tasted abnormally salty, predict that the infant was destined to die of pulmonary congestion and its side effects. Quinton (1983) and Knowles et al. (1983) first suggested that the primary defect of cystic fibrosis may be in chloride transport. Widdicombe et al. (1985) demonstrated a cyclic AMP-dependent transepithelial chloride current in normal but not CF epithelia. The pathophysiology of cystic fibrosis, specifically the impermeability of epithelia to chloride ion, was reviewed by Welsh and Fick (1987).

Landry et al. (1989) purified several proteins from kidney and trachea that exhibit chloride channel activity when they are reconstituted into artificial phospholipid bilayer membranes. One or more of these proteins may turn out to be all or part of the secretory chloride channel that is defective in CF. Using antibodies against CFTR peptides, Marino et al. (1991) demonstrated that the CFTR molecule is located in and confined to the apical domain of pancreatic centroacinar and intralobular duct cells. From this they concluded that the proximal duct epithelial cells play a key role in the early events leading to pancreatic insufficiency in CF and that apical chloride transport by these cells is essential for normal pancreatic secretory function. Jetten et al. (1989) created a stable human airway epithelial cell line by retroviral transformation of CF airway epithelium. They found that it maintains the defect in the secretory chloride channel. Rich et al. (1990) expressed the CFTR gene in cultured cystic fibrosis airway epithelial cells and assessed chloride ion channel activation in single cells by means of a fluorescence microscopic assay and a patch-clamp technique. In cells from patients with CF, expression of the CFTR gene but not of the mutant form corrected the chloride ion channel defect. Since there is no animal model for CF, the authors viewed the cell line as very important in studies of the basic defect and for screening of candidate genes which would complement the defect and thus identify the site of the mutation. Bradbury et al. (1992) raised the question as to whether there may be more to the pathogenesis of cystic fibrosis than merely a defect in chloride passage across cell membranes and the concomitant defect in secretion of water.

Two hypotheses, 'hypotonic (low salt)/defensin' and 'isotonic volume transport/mucus clearance,' attempt to link defects in cystic fibrosis transmembrane conductance regulator-mediated ion transport to CF airways disease. Matsui et al. (1998) tested these hypotheses with planar and cylindrical culture models and found no evidence that the liquids lining airway surfaces were hypotonic or that salt concentrations differed between CF and normal cultures. In contrast, CF airway epithelia exhibited abnormally high rates of airway surface liquid absorption, which depleted the periciliary liquid layer and abolished mucus transport. The failure to clear thickened mucus from airway surfaces likely initiates CF airways infection. These data indicate that therapy for CF lung disease should not be directed at modulation of ionic composition, but rather at restoring volume (salt and water) on airway surfaces.

Reddy et al. (1999) demonstrated that in freshly isolated normal sweat ducts, epithelial sodium channel (ENaC; see 600228) activity is dependent on, and increases with, CFTR activity. Reddy et al. (1999) also found that the primary defect in chloride permeability in cystic fibrosis is accompanied secondarily by a sodium conductance in this tissue that cannot be activated. Thus, reduced salt absorption in cystic fibrosis is due not only to poor chloride conductance but also to poor sodium conductance.

Kravchenko et al. (2008) showed that a bacterial small molecule, N-(3-oxo-dodecanoyl) homoserine lactone (C12), selectively impairs the regulation of NF-kappa-B (see 164011) functions in activated mammalian cells. The consequence is specific repression of stimulus-mediated induction of NF-kappa-B-responsive genes encoding inflammatory cytokines and other immune regulators. Kravchenko et al. (2008) concluded that their findings uncovered a strategy by which C12-producing opportunistic pathogens such as P. aeruginosa attenuate the innate immune system to establish and maintain local persistent infection in humans, for example, in cystic fibrosis patients.

Diagnosis

Boue et al. (1986) reported on prenatal diagnostic studies in 200 pregnancies with a presumed 1-in-4 risk of recurrence of cystic fibrosis. The method involved measurement of total enzymes and isoenzymes of gamma-glutamyl-transpeptidase, aminopeptidase M, and alkaline phosphatase in amniotic fluid in the second trimester. The recurrence rate of cystic fibrosis was 22.5% in 147 cases in which the index case had cystic fibrosis without meconium ileus at birth but was 47.5% when the index case had meconium ileus. The authors speculated on the mechanism of the 50% recurrence rate and favored the view that 1 parent was in fact a homozygote for a mild allele. With use of their method, the authors suggested 98% accuracy in prenatal diagnosis of cystic fibrosis. Allan et al. (1981), Super (1987), and Boue et al. (1986) found that in families in which a CF child did not have meconium ileus the observed recurrence rate agreed with the expected 1-in-4 risk, but that in families with a history of meconium ileus in the index case the recurrence rate was much higher, 43.7% in the study of Boue et al. (1986). Mornet et al. (1989) found different haplotype associations in the 2 types of families. A distortion of the segregation ratio was suggested to explain the high recurrence rate. Estivill et al. (1987) pointed out that individuals with haplotypes A and C as determined by their cosmid library, whether homozygous or heterozygous, have a considerably reduced risk of being carriers as compared to the 1 in 20 average risk in the British population. On the other hand, a homozygote for haplotype B had a risk of about 1 in 7 of being a carrier. It appears that about 85% of cases of CF in northern Europeans have 1 particular haplotype and the rest a second haplotype. CF with or without meconium ileus may be different entities. Baxter et al. (1988) stated that the meconium ileus form of CF is often lethal so that families with this form are underrepresented in linkage studies. On the other hand, couples who seek prenatal diagnosis often have had children with this problem. Harris et al. (1988) found that 30 of 37 British CF families were sufficiently informative with 3 RFLP probes to enable prenatal diagnosis. They also used linkage analysis to exclude CF in 2 cases in which diagnosis of the disease was equivocal in the sib of an affected child.

Strain et al. (1988), Krawczak et al. (1988), and Beaudet et al. (1989) discussed the use of linkage disequilibrium between CF and DNA markers in genetic risk calculation. Handyside et al. (1992) achieved preimplantation diagnosis. In vitro fertilization techniques were used to recover oocytes from each of 3 women and fertilize them with the husband's sperm. Both members of the 3 couples carried the delF508 mutation. Three days after insemination, embryos in the cleavage stage underwent biopsy with removal of 1 or 2 cells for DNA amplification and analysis. In 2 of the women the oocytes produced noncarrier, carrier, and affected embryos. Both couples chose to have 1 noncarrier embryo and 1 carrier embryo transferred. One woman became pregnant and gave birth to a girl free of the deletion in both chromosomes. Curnow (1994) used cystic fibrosis to illustrate how, in genetic counseling, one can calculate carrier risk for recessive diseases when not all the mutant alleles are detectable. Dean (1995) reviewed the 5 main methods used for detecting mutations at the time.

Savov et al. (1995) demonstrated the presence of 2 different mutations carried by the same CF allele in 4 out of 44 Bulgarian CF patients during a systematic search of the entire coding sequence of the CFTR gene. Two of the double mutant alleles include 1 nonsense and 1 missense mutation, and although the nonsense mutation could be considered to be the main defect, the amino acid substitutions are candidates for disease-causing mutations as well. Savov et al. (1995) suggested that double mutant alleles may be more common than expected and could account for some of the problems in phenotype-genotype correlations. Stern (1997) reviewed the diagnosis of cystic fibrosis. He presented a table of conditions, all readily distinguishable from cystic fibrosis, that can cause moderately elevated sweat electrolytes. With mutation analysis, in approximately 1% of cases no abnormal gene can be found and in about 18% more only 1 abnormal gene will be identified. Stern (1997) pointed out, however, that even if both genes were abnormal, the patient could have an ameliorating or neutralizing second mutation elsewhere. For example, patients homozygous for delF508 (602421.0001) have normal sweat electrolyte concentrations if a second mutation, R553Q (602421.0121), is also present.

Screening

Under the chairmanship of Beaudet and Kazazian (1990), a workshop at the National Institutes of Health laid down guidelines concerning screening for the cystic fibrosis gene. The following points were emphasized: screening should be voluntary, and confidentiality must be assured; screening requires informed consent; providers of screening services have an obligation to ensure adequate education and counseling; quality control in all aspects of testing is required; and there should be equal access to testing.

Newborn babies with CF have abnormally high levels of immunoreactive trypsin (IRT) in serum, which has been the basis for a screening test. Hammond et al. (1991) reported on the results of a Colorado statewide test of the feasibility and efficacy of measuring immunoreactive trypsinogen in blood spots to screen for neonatal cystic fibrosis. They found an incidence of cystic fibrosis of 1 in 3,827 (0.26 per 1,000), with 3.2 newborns per 1,000 requiring repeat measurements. When adjusted for race and compliance with testing, the incidence among the white infants (1 in 2,521) was close to the expected incidence. They concluded that screening was feasible and could be implemented with acceptable rates of repeat testing and false positive and false negative results. Laroche and Travert (1991) found 9 F508 deletion heterozygotes among 149 infants with neonatal transitory mild hypertrypsinemia. Dumur et al. (1990) found an increased frequency of heterozygosity for the same mutation in adults with chronic bronchial hypersecretion.

Observing that many patients with cystic fibrosis are malnourished by the time the diagnosis is made, Farrell et al. (1997) sought to determine whether newborn screening and early treatment might prevent the development of nutritional deficiency. A total of 650,341 newborn infants were screened by measuring immunoreactive trypsinogen on dried blood spots (from April 1985 through June 1991) or by combining the trypsinogen test with DNA analysis (from July 1991 through June 1994). Of 325,171 infants assigned to an early-diagnosis group, cystic fibrosis was diagnosed in 74 infants, including 5 with negative screening tests. Excluding infants with meconium ileus, Farrell et al. (1997) evaluated nutritional status for up to 10 years by anthropometric and biochemical methods in 56 of the infants who received an early diagnosis and in 40 of the infants in whom the diagnosis was made by standard methods (the control group). Pancreatic insufficiency was managed with nutritional interventions that included high-calorie diets, pancreatic enzyme therapy, and fat-soluble vitamin supplements. The diagnosis of cystic fibrosis was confirmed by a positive sweat test at a younger age in the early-diagnosis group than in the control group (mean age, 12 vs 72 weeks). At the time of diagnosis, the early-diagnosis group had significantly higher height and weight percentiles and a higher head circumference percentile. The early-diagnosis group also had significantly higher anthropometric indices during the follow-up, especially the children of pancreatic insufficiency and those who were homozygous for the delta-F508 mutation. Dankert-Roelse and te Meerman (1997) raised the question of whether the time had not arrived for adoption of routine neonatal screening for cystic fibrosis.

Farrell et al. (2001) reported findings of the continuation of their longitudinal study of children with CF detected by neonatal screening or standard clinical methods (control). Because sequential analysis of nutritional outcome measures revealed significantly better growth in screened patients, the authors accelerated the unblinding of the control group and identified 9 additional CF patients. After each member of this cohort had been enrolled for at least 1 year, Farrell et al. (2001) performed another statistical analysis of anthropometric indices. They found that severe malnutrition persisted after delayed diagnosis of CF and questioned whether catch-up growth is possible.

Muller et al. (1998) studied 209 fetuses with hyperechogenic bowel diagnosed at routine ultrasonography and with no family history of cystic fibrosis. Seven of the 209 fetuses (3.3%) were subsequently given the diagnosis of cystic fibrosis. Muller et al. (1998) pointed out that this incidence is 84 times the estimated risk of cystic fibrosis in the general population, and concluded that screening for cystic fibrosis should be offered to families in which fetal hyperechogenic bowel is diagnosed at routine ultrasonography.

Boyne et al. (2000) demonstrated that of 88 neonates with transient hypertrypsinemia shown to carry a delta-F508 mutation, 20 (22%) carried a second CFTR mutation. In 45% of cases, the second mutation was R117H (602421.0005). Forty-one percent of delta-F508 heterozygous neonates with greater than 25 ng IRT/ml in the 27th day blood sample possessed a second mutation, compared to approximately 6% of those with less than 25 ng/ml. Boyne et al. (2000) concluded that the IRT level at 27 days is a useful marker to refine the risk of finding a second CFTR mutation in delta-F508 heterozygotes with hypertrypsinemia.

Castellani et al. (2001) studied 47 neonates with hypertrypsinemia and normal sweat chloride. Thirty-two of the newborns had 1 identified CFTR mutation. Further analysis by DGGE identified additional mutations in 14 of the 32 babies in whom a mutation had previously been found. In 1 case, 2 more CFTR gene mutations were identified. Mutations were identified in 8 of the 15 babies in whom a mutation had previously not been identified. Castellani et al. (2001) pointed out that it is impossible to predict the clinical outcome of these newborns and suggested that in some cases these findings might represent CFTR-related disease even in the presence of normal sweat chloride. They therefore advocated close clinical follow-up of neonates in this group.

Scotet et al. (2002) evaluated the prenatal detection of CF by ultrasound in more than 346,000 pregnancies in Brittany, France, where the incidence of CF is very high. The authors found that the incidence of CF in fetuses with echogenic bowel was 9.9%, significantly higher than in the general population. Only severe mutations were identified in these fetuses. The ultrasound examination enabled diagnosis of 11% of affected fetuses. Scotet et al. (2002) concluded that CF screening based on ultrasound examination is effective, particularly in populations where the disease is frequent.

Dequeker et al. (2009) provided an update on the best practice guidelines for the molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders, as established at a 2006 conference in Manchester, U.K. The report included methods for CFTR mutation testing, indications for CFTR testing, and guidelines for interpretation.

De Becdelievre et al. (2011) reported on an 18-year experience of documenting comprehensive CFTR genotypes and correlations with ultrasound patterns in a series of 694 cases of fetal bowel anomalies. A total of 30 CF fetuses and 8 cases compatible with CFTR-related disorders were identified. CFTR rearrangements were found in 5 of the 30 CF fetuses. A second rare mutation indicative of CF was found in 21.2% of fetuses carrying a frequent mutation. The frequency of CF among fetuses with no frequent mutation was 0.43%. Correlation with ultrasound patterns revealed a significant frequency of multiple bowel anomalies in CF fetuses. The association of at least 2 signs of bowel anomaly on ultrasound, including hyperechogenic bowel, loop dilatation, and/or nonvisualization of gallbladder, was observed in 14 of 30 CF fetuses (46.7%) as compared with 61 of 422 (14.5%) non-CF fetuses (P less than 10(-3)). The rare triad of hyperechogenic bowel, loop dilatation, and nonvisualization of the gallbladder was of the highest diagnostic value, with a likelihood ratio of 31.40. Fetuses demonstrating this triad of bowel anomalies should have extensive CFTR sequencing and a search for rearrangements, even if no common mutation is detected.

Clinical Management

Cleghorn et al. (1986) obtained good results from oral administration of a balanced solution rendered nonabsorbable by addition of polyethylene glycol.

Hubbard et al. (1992) reported on the use of human deoxyribonuclease I produced by recombinant DNA techniques for cleaving DNA in the sputum of patients with cystic fibrosis and thereby reducing sputum viscosity. Improvement of lung function was documented.

Rosenfeld et al. (1992) evaluated the direct transfer of the normal CFTR gene to airway epithelium using a replication-deficient recombinant adenovirus (Ad) vector containing normal human CFTR cDNA (Ad-CFTR). Two days after in vivo intratracheal introduction of Ad-CFTR in cotton rats, in situ analysis demonstrated human CFTR gene expression in lung epithelium. Northern analysis of lung RNA revealed human CFTR transcripts for up to 6 weeks. Human CFTR protein was detected in epithelial cells using anti-human CFTR antibody 11 to 14 days after infection. While the safety and effectiveness remained to be demonstrated, these observations suggested the feasibility of in vivo CFTR gene transfer as therapy for the pulmonary manifestations of CF.

Hyde et al. (1993) illustrated the feasibility of gene therapy for the pulmonary aspects of CF in humans. They used liposomes to deliver a CFTR expression plasmid to epithelia of the airway and to alveoli deep in the lung, leading to the correction of the ion conductance defects found in the trachea of transgenic (cf/cf) mice. Yang et al. (1993) described a similar approach to the treatment of hepatobiliary disease of cystic fibrosis. In situ hybridization and immunocytochemical analysis of rat liver sections indicated that the endogenous CFTR gene is primarily expressed in the intrahepatic biliary epithelial cells. To target recombinant genes specifically to the biliary epithelium in vivo, Yang et al. (1993) infused recombinant adenoviruses expressing lacZ or human CFTR into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days.

Crystal et al. (1994) administered a recombinant adenovirus vector containing the normal human CFTR cDNA to the nasal and bronchial epithelium of 4 individuals with CF. They found that the vector can express the CFTR cDNA in the CF respiratory epithelium in vivo. With doses up to 2 x 10(9) pfu, there was no recombination/complementation or shedding of the vector or rise of neutralizing antibody titers. At 2 x 10(9) pfu, a transient systemic and pulmonary syndrome was observed. The syndrome was thought to have been caused by vector-induced inflammation of the lower respiratory tract and was possibly induced by interleukin-6, which was found at high levels in the serum of a patient. Follow-up at 6 to 12 months demonstrated no long-term adverse effects. Crystal et al. (1994) concluded that correction of the CF phenotype in the airway epithelium might be achieved with this approach.

A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis by Knowles et al. (1995) yielded less encouraging results than those predicted by Crystal et al. (1994). Knowles et al. (1995) did not succeed in correcting the functional defects in nasal epithelium and local inflammatory responses limited the dose of adenovirus that could be administered to overcome the inefficiency of gene transfer. Wilson (1995) reviewed gene therapy for cystic fibrosis. Transplantation of ex vivo manipulated stem cells was the concept of gene therapy used in ADA deficiency (102700). Wide distribution of possible cellular targets for gene therapy in the CF lung and the absence of a known lung epithelial stem cell suggested that an ex vivo approach to gene therapy would not be feasible. Therefore research focused on in vivo approaches for gene transfer that could conveniently be delivered into the airway via aerosols.

Boucher (1999) reviewed the status of gene therapy for CF lung disease.

Smyth et al. (1994) described colonic strictures, later referred to as fibrosing colonopathy, in children with cystic fibrosis. The patients presented with intestinal obstruction and required surgical resection of a thickened and narrowed area of the colon. The only aspect of these children's management that had changed was a switch to new 'high strength' pancreatic enzyme preparations about 12 months previously. It was not clear whether the preparation was responsible for the problem or whether this was a part of the pathology of cystic fibrosis. In some instances, the clinical and radiologic features were suggestive of Crohn disease or an inflammatory colitis, but the histologic findings were strikingly different (Smyth, 1996). The stenoses, which are frequently long segment, result from submucosal thickening by fibrous connective tissue. This leads to intraluminal narrowing which occurs without a significant reduction in the external diameter of the colon. The epithelium is generally intact with very little inflammatory change in the affected areas. FitzSimmons et al. (1997) studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy that required colectomy for colonic strictures and compared the patients with 105 controls (mean age 5.2 years) who were other patients with cystic fibrosis matched for age at the time of surgery and who did not have fibrosing colonopathy. They found that the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with the dose of 0 to 24,000 units per kilogram per day, was 10.9, and relative risk associated with a dose of more than 50,000 units per kilogram per day was 199.5. The findings were considered to support the recommendation that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

In a multicenter, randomized, controlled, crossover trial of prepubertal children with cystic fibrosis, Hardin et al. (2006) found that treatment with recombinant human growth hormone (rhGH) improved height and weight, decreased the number of hospitalizations, and improved quality of life in 32 children who received the treatment compared to 29 children not treated. These effects were sustained after rhGH was discontinued.

Population Genetics

Attempting total ascertainment of cases in white children born alive in Ohio during the years 1950 through 1953, Steinberg and Brown (1960) estimated the phenotype frequency to be about 1 in 3,700, a value only about one-fourth that of some earlier estimates. Cystic fibrosis even at this lower estimate is the most frequent lethal genetic disease of childhood. The gene frequency was estimated to be about 0.016, and about 3% of white persons are heterozygotes.

Klinger (1983) found an incidence of 1 in 569 among 10,816 live births in the Old Order Amish of Holmes County, Ohio. The gene frequency was estimated to be at least 0.042. On the other hand, not a single case was found among 4,448 live births in the Geauga County, Ohio, Amish. In Connecticut, Honeyman and Siker (1965) arrived at higher phenotype frequency estimates of 1 in 489 (maximal) and 1 in 1,863 (minimal).

Bois et al. (1978) reported a frequency of at least 1 in 377 births in an area of Brittany, France. Scotet et al. (2002) retrospectively registered all 520 CF patients born in Brittany since 1960. The birthplace of the patients, the spectrum of CFTR mutations, and the spatial distribution of the mutations across Brittany were determined. The incidence of CF was 1 in 2,630, with a west/east gradient that was confirmed over time (1 in 2,071 in the west, 1 in 3,286 in the east). At the time of study, the incidence of CF was decreasing, mainly as a result of prenatal diagnosis. A mutation detection rate of 99.7% was obtained. Western Brittany presented a specific spectrum of mutations, whereas the eastern region showed a spectrum more similar to the overall picture in France.

In Italy, to estimate the incidence of CF, Romeo et al. (1985) used the increase in first- and second-cousin parentage, as compared with the general level of consanguinity indicated by the archive of consanguineous marriages maintained by the Catholic Church. The incidence was estimated to be about 1/2000. The data were consistent with a single gene locus; consanguinity would have been higher if more than one were present. The segregation ratio in 624 CF sibships was 0.252.

In Hutterite families with cystic fibrosis, Ober et al. (1987) found close linkage to chromosome 7 markers as in non-Hutterite families. Because 3 different chromosome 7 haplotypes carried the CF mutation in these families, they suggested that the CF gene may have been introduced into the Hutterite population by as many as 3 different ancestors. Fujiwara et al. (1989) confirmed these observations.

From studies in Caucasian families in Utah, Jorde and Lathrop (1988) concluded that fertility differences are unlikely to account for the observed Caucasian CF gene frequency. They compared 143 grandparent couples of Utah CF cases with 20 replicate sets of matched control couples drawn from the Utah Genealogical Database. Before ascertainment correction was applied, CF carriers appeared to manifest a significant fertility advantage over controls. After the correction formula (not used in previous studies) was applied, this difference disappeared. Also, no differences were found between carriers and controls in the length of intervals between births.

In the Hutterites, Klinger et al. (1990) demonstrated that 1 of the 3 previously identified CF haplotypes carries the phe508 deletion. The other 2 Hutterite CF haplotypes are generally rare in Caucasian populations and must carry different CF mutations. Thus, there must have been at least 3 original carriers of CF mutations among the founders of the Hutterite population. They found 1 Hutterite CF patient who had both of the haplotypes that do not carry the phe508 deletion.

From a study in Northern Ireland, Hill et al. (1989) concluded that the CF locus is in strong linkage disequilibrium with KM19 and Xv-2C, as it is in other Caucasian populations. These findings indicate that CF in northern European populations may have resulted from a single ancestral mutation. A further finding was preferential inheritance of the paternal CF allele (22 of 28) as opposed to the maternal CF allele (6 of 28) with no significant difference in the sex of the children inheriting these alleles. Cutting et al. (1989) concluded from the analysis of closely linked DNA marker haplotypes that the majority of CF mutations in the Caucasian population arose from a single mutational event. Similar analysis in American black families suggested that multiple mutant alleles are found in this population.

Although CF had been thought to be very rare in Arabs, Nazer et al. (1989) documented CF in 13 children in Saudi Arabia. El-Harith et al. (1998) reported that 6 mutations, detectable by PCR with subsequent restriction enzyme digestion, would allow detection of 70% of Saudi CFTR mutations.

Estivill et al. (1989) reported that in Spanish and Italian populations, deletion of phe508 is present in only 46.2% of CF chromosomes. In all cases, it occurred with haplotype 2, which accounts for about 75% of southern European CF chromosomes; thus, at least 2 independent mutations must have occurred on this haplotype. McIntosh et al. (1989) found a frequency of 74.4% for the phe508 deletion in Scotland. Colten (1990) indicated that one-third of the more than 15,000 patients listed in the registry of the North American National Cystic Fibrosis Foundation are older than 21 years.

Using PCR and hybridization with allele-specific oligonucleotides, Lemna et al. (1990) found the phe508 deletion in 75.8% of 439 cystic fibrosis chromosomes. The 3-base deletion was found in only 30.3% of cystic fibrosis chromosomes from Ashkenazi families. In 5 southern European populations (Albanian, Greek, Italian, Spanish, and Yugoslavian), Nunes et al. (1991) found that, apart from delF508, the most frequent mutations were G542X (602421.0009), 6.04%; R1162X (602421.0033), 3.61%; and N1303K (602421.0032), 3.24%. Of the 14 mutations tested, 7 others had frequencies of less than 1% and 4 mutations were not found at all.

Ten Kate et al. (1991) demonstrated that consanguinity, even if present, may be irrelevant: a family with 2 brothers with cystic fibrosis whose parents were consanguineous, being members of an isolated religious group, were found to have inherited different mutations from the parents. They presented a diagram relating the likelihood of 'autozygosity,' depending on gene frequency with consanguinity of various degrees.

In a systematic study of 365 CF chromosomes in the Celtic population in Brittany, Ferec et al. (1992) identified more than 98% of the cystic fibrosis gene mutations. By use of the denaturing gradient gel electrophoresis (DGGE) method, they detected 19 different CFTR mutations located in 9 exons. Nine new mutations were found.

Kerem et al. (1995) reported that the incidence of CF and the frequency of disease-causing mutations varies considerably among the Jewish ethnic subgroups in Israel. Among Ashkenazi Jews, the frequency of CF is 1:3300, which is similar to the frequency in most Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a similar frequency among Jews from Libya (1:2700), Georgia (1:2700), Greece and Bulgaria (1:2400), but is rare in Jews from Yemen (1:8800), Morocco, (1:15000), Iraq (1:32000), and Iran (1:39000). To that point, only 12 mutations had been identified in Israeli Jews, and this enabled the identification of 91% of the CF chromosomes in the entire Jewish CF population. However, in each Jewish ethnic group, the disease is caused by a different repertoire of mutations.

In a study in the Netherlands, de Vries et al. (1997) tested for the carrier frequency of the delta-F508 mutation by analyzing mouthwashes and matched blood samples from 11,654 blood donors from all over the country. They detected a delF508 carrier frequency of 1 in 42 (95% CI 1/37-1/47). By assuming that the relative frequency of the delF508 mutation among carriers and patients is comparable in the Netherlands, they estimated the overall CF carrier frequency as 1 in 32, significantly less than 1 in 25, the usual figure cited. An increase in carrier frequency with increasing distance from the northeastern region of the country was observed, thus confirming that there is a gradient in gene frequency with low frequencies in the northeastern part of the country and high frequencies in the southern part.

Brock et al. (1998) studied a total of 27,161 women enrolled in prenatal clinics in Scotland between 1990 and 1997. All 27,161 were screened for the delta-F508 (602421.0001), G551D (602421.0013), and G542X (602421.0009) mutations. In 14,360 women R117H was also measured. In addition, 183 patients with cystic fibrosis were studied for the presence of these mutations. Based on their data, the authors estimated that the incidence of CF in the Scottish population is 1 in 1984, with 95% confidence intervals between 1 in 1,692 to 1 in 2,336.

Macek et al. (1997) reported a large-scale study for mutation identification in African American CF patients. The entire coding and flanking intronic sequence of the CFTR gene was analyzed by denaturing gradient-gel electrophoresis (DGGE) and sequencing in 82 African American CF chromosomes. One novel mutation, 3120+1G-A (602421.0120), occurred with a frequency of 12.3% and was also detected in a native African patient. To establish gene frequencies, an additional group of 66 African American CF chromosomes were screened for mutations identified in 2 or more African American patients. Screening for 16 'common Caucasian' mutations identified 52% of CF alleles in African Americans, while screening for 8 'common African' mutations accounted for an additional 23%. The combined detection rate of 75% was comparable to the sensitivity of mutation analysis in Caucasian CF patients. These results indicated that African Americans have their own set of 'common' CF mutations that originated from the native African population.

To examine whether the 3120+1G-A mutation has a common origin in the diverse populations in which it has been observed or whether its widespread distribution is the result of recurrent mutational events, Dork et al. (1998) analyzed DNA samples obtained from 17 unrelated CF patients in 4 different populations and from 8 unrelated African CF carriers. They found identical extended CFTR haplotypes for the 3120+1G-A alleles in Arab, African, and African American patients, strongly suggesting that the mutation had a common origin. This finding was not surprising in the case of Africans and African Americans; it was not as easy to explain the presence of the 3120+1G-A mutation in African and Saudi Arab patients. Recent ethnic admixture accounts for a few percent of Africans in Saudi Arabia; however, this was considered an unlikely explanation of the finding, since none of the Saudi families with the mutation had any anthropomorphologic signs of an African descent. In the past, a continuous gene flow between Arab and African populations probably persisted for many centuries, in association with trading and with the spread of the Islamic religion. Thus far, the Greeks are the only Caucasian population in which the 3120+1G-A mutation has been identified. A recurrent mutational event seems to be unlikely, because the Greek haplotype differs from the others in only minor respects. Historical contacts, e.g., under Alexander the Great or during the ancient Minoan civilization, may provide an explanation for the common ancestry of the disease mutation in these ethnically diverse populations. Dork et al. (1998) concluded that 3120+1G-A is an ancient mutation that may be more common than previously thought in populations of the tropical and subtropical belt, where CF probably is an underdiagnosed disorder.

Padoa et al. (1999) screened 1,152 unrelated, healthy African blacks from southern, western, and central Africa, and 9 black CF patients for the 3120+1G-A mutation. The mutation was found to have a carrier frequency of 1 in 91 for South African blacks, with a 95% confidence interval of 1 in 46 to 1 in 197. A subset of those studied were also screened for the A559T, S1255X, and 444delA mutations. These mutations were not found in any of the patients or in over 373 healthy subjects tested. Padoa et al. (1999) concluded that the corrected CF carrier frequency in South African blacks would be between 1 in 14 and 1 in 59 and, hence, that the incidence of CF would be predicted to be between 1 in 784 and 1 in 13,924 in this population. Padoa et al. (1999) speculated as to why the observed incidence in this population is lower than that which they predicted.

Restrepo et al. (2000) used a reverse dot-blot detection kit to examine the frequency of 16 CFTR mutations among 192 cystic fibrosis alleles in Mexico, Colombia, and Venezuela. The detection efficacy of the panel used was 47.9% in this population. The most prevalent CF allele was delF508 (39.6%). The most common alleles among the others were G542X, N1303K and 3849+10kbC-T (602421.0062). The authors compared their results to population studies from Spain and concluded that an important Spanish contribution is present in CFTR mutations in these 3 countries, but that important regional differences in allele prevalence exist.

Kabra et al. (2000) analyzed CFTR mutations in 24 children with CF from the Indian subcontinent. Of the mutant chromosomes, 33.3% had the delF508 mutation. The authors screened 16 exons of the CFTR gene by SSCP and heteroduplex analysis, but mutations were not identified in 46% of chromosomes. The authors also reported novel mutations in their population: 3622insT (602421.0125) and 3601-20T-C (602421.0126).

Wang et al. (2000) found that 7 of 29 Hispanic patients with CF were heterozygous for a single-basepair deletion at nucleotide 3876 resulting in a frameshift and termination at residue 1258 of the CFTR gene (602421.0127). This mutation therefore accounted for 10.3% of mutant alleles in this group. The patients with this mutation had a severe phenotype as determined by age of diagnosis, high sweat chloride, presence of allergic bronchopulmonary aspergillosis, pancreatic insufficiency, liver disease, cor pulmonale, and early death. Wang et al. (2000) also noted that this mutation had not been reported in any other ethnic group.

Considering that the haplotype background of the mutations that most often cause cystic fibrosis in Europe is different from that of non-CF chromosomes, Mateu et al. (2002) reasoned that these haplotype backgrounds might be found at high frequencies in populations in which CF was currently not common; thus, such populations would be candidates for the place of origin of CF mutations. In a worldwide survey of normal chromosomes, they found a very low frequency or absence of the most common CF haplotypes in all populations analyzed, and a strong genetic variability and divergence, among various populations, of the chromosomes that carry disease-causing mutations. They suggested that the depth of the gene genealogy associated with disease-causing mutations may be greater than that of the evolutionary process that gave rise to the current human populations. The concept of 'population of origin' lacks either spatial or temporal meaning for mutations that are likely to have been present in Europeans before the ethnogenesis of the current populations. Subsequent population processes may have erased the traces of their geographic origin.

In Brittany, France, Scotet et al. (2003) reviewed the results of a neonatal screening program for CF begun in 1989 to determine the prevalence of CF at birth and to review data from prenatal diagnoses carried out in the region, first in families related to a CF child and also those made following the detection of an echogenic bowel upon routine ultrasound examination performed during pregnancy. The prevalence of CF at birth was estimated to be 1 in 2,838 in the region from 1992 to 2001. By including the 54 CF-affected pregnancies that were terminated during those 10 years, the corrected birth prevalence of CF was 1 in 1,972. Prenatal diagnosis was therefore responsible for a decrease in CF prevalence at birth of 30.5%.

Quint et al. (2005) described the mutation spectrum in Jewish CF patients living in Israel. Using a panel of 12 CFTR mutations, they identified 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jews of North African origin, and 75% in Jewish patients from Iraq.

In a survey of 495 blood samples of randomly selected healthy individuals in Hanoi, Vietnam, Nam et al. (2005) found no instance of the delta-F508 mutation.

Evolution

Hansson (1988) speculated that if the defect in the control of apical membrane chloride ion channels in CF extends to the intestine, a resistance to bacterial toxin-mediated diarrhea might confer a selective advantage on carriers for the CF gene. Baxter et al. (1988) presented actual observations indicating that intestine in CF homozygotes fails to exhibit a secretory response on exposure to bacterial toxins that would normally induce a secretory diarrhea. They were proceeding to investigate intestinal secretory responses of heterozygotes. The high frequency of the CF gene might be explained by this mechanism. Romeo et al. (1989) also suggested that a selective advantage consisting of high resistance to chloride-ion-secreting diarrheas might have favored, in the past, survival of infants heterozygous for the CF gene.

McMillan et al. (1989) demonstrated an apparent association between heterozygosity at the cystic fibrosis locus and heterozygosity for a RFLP near the constant region of the T-cell receptor beta chain (186930). They suggested that this previously unreported disease association might indicate some form of epistatic interaction between the CF gene and the TCRB gene such that the double heterozygote is immunologically advantaged.

Rodman and Zamudio (1991) suggested that resistance to cholera may have been the environmental factor that selected CF heterozygotes over their 'normal' homozygote cohort. This suggestion obtained experimental support from the observations of Gabriel et al. (1994). In a study of the CFTR -/- mouse, created by disruption by the CFTR gene at exon 10 by insertion of an in-frame stop codon to replace ser489, they found that transgenic mice that expressed no CFTR protein did not secrete fluid in response to cholera toxin. Heterozygotes expressed 50% of the normal amount of CFTR protein in the intestinal epithelium and secreted 50% of the normal fluid and chloride ion in response to cholera toxin. The findings suggested that CF heterozygotes may possess a selective advantage of resistance to cholera.

Pier et al. (1998) investigated whether increased resistance to typhoid fever in the heterozygote could be a factor in maintaining mutant CFTR alleles at high levels in selected populations. Typhoid fever is initiated when Salmonella typhi enters gastrointestinal epithelial cells for submucosal translocation. They found that S. typhi, but not the related murine pathogen S. typhimurium, uses CFTR for entry into epithelial cells. Cells expressing wildtype CFTR internalized more S. typhi than isogenic cells expressing the most common CFTR mutation, delF508 (602421.0001). Monoclonal antibodies and synthetic peptides containing a sequence corresponding to the first predicted extracellular domain of CFTR inhibited uptake of S. typhi. Heterozygous delF508 Cftr mice translocated 86% fewer S. typhi into the gastrointestinal submucosa than did wildtype Cftr mice; no translocation occurred in delF508 Cftr homozygous mice. The Cftr genotype had no effect on the translocation of S. typhimurium. Immunoelectron microscopy revealed that more CFTR bound S. typhi in the submucosa of Cftr wildtype mice than in delF508 heterozygous mice. Pier et al. (1998) concluded that diminished levels of CFTR in heterozygotes decreases susceptibility to typhoid fever.

Van de Vosse et al. (2005) tested the hypothesis that CFTR heterozygotes have a selective advantage against typhoid, which may be conferred through reduced attachment of S. typhi to the intestinal mucosa. They genotyped patients and controls in a typhoid endemic area in Indonesia for 2 highly polymorphic markers in CFTR and the most common CF mutation, F508del. Consistent with the apparently very low incidence of CF in Indonesia, the F508del mutation was not present in any patients or controls. However, they found significant association between a common polymorphism in intron 8 (16 or 17 CA repeats) and selective advantage against typhoid.

Hogenauer et al. (2000) used an intestinal perfusion technique to measure in vivo basal and prostaglandin-stimulated jejunal chloride secretion in normal subjects, CF heterozygotes, and patients with CF. Patients with CF had essentially no active chloride secretion in the basal state, and secretion was not stimulated by a prostaglandin analog. However, CF heterozygotes secreted chloride at the same rate as did people without a CF mutation. If heterozygotes are assumed to have less than normal intestinal CFTR function, these results mean that CFTR expression is not rate limiting for active chloride secretion in heterozygotes. The results did not support the theory that the very high frequency of CF mutations is due to a survival advantage that is conferred on heterozygotes who contract diarrheal diseases mediated by intestinal hypersecretion of chloride, such as infection with Vibrio cholerae or E. coli.

Genotype/Phenotype Correlations

Wine (1992) pointed out that CFTR mutations associated with pancreatic sufficiency, milder pulmonary disease, and improved sweat gland function are associated with residual CFTR chloride-ion channel function. He questioned the disruptive effects proposed for the delF508 mutation because variation in homozygotes for this mutation is very large. At the same time, those homozygous for stop codons have been severely affected, showing pancreatic insufficiency and pulmonary function values (FEV1) in the same range as those of delF508 subjects. Disruptive effects of delF508 would be expected to give rise to a dominant pattern of inheritance. Wine (1992) concluded that the observations are consistent with the recessive nature of CF and with the likelihood that gene or protein replacement therapy for CF will be effective on their own, without requiring concomitant silencing of the delF508 gene. Sheppard et al. (1993) found that some CFTR mutations, such as delF508, which disrupt normal processing and hence are missing from the apical membrane, generate no chloride current and are associated with severe disease. Other mutants, such as R117H (602421.0005), R334W (602421.0034), and R347P (602421.0006), which are correctly processed and retain significant apical chloride channel function, are associated with a milder form of the disease. Thus, the CF genotype determines the biochemical abnormality, which determines the clinical phenotype. Because these 3 'mild' mutants have normal regulation, interventions designed to increase the activity of mutant CFTR may have therapeutic efficacy in patients with these mutations. Studying 267 children and adolescents with CF who were regularly seen at the same center, Kubesch et al. (1993) found that the age-specific colonization rates with Pseudomonas aeruginosa were significantly lower in pancreatic sufficient than in pancreatic insufficient patients. The missense and splice site mutations that were 'mild' CF alleles with respect to exocrine pancreatic function were also 'low risk' alleles for the acquisition of P. aeruginosa. On the other hand, the proportion of P. aeruginosa-positive patients increased most rapidly in the pancreatic insufficient delF508 compound heterozygotes who were carrying a termination mutation in the nucleotide binding fold-encoding exons.

Kulczycki et al. (2003) stated that their oldest patient was a 71-year-old white male who was diagnosed with CF at the age of 27 years because of recurrent nasal polyposis, elevated sweat sodium and chloride, and a history of CF in his 20-year-old sister. The man was married but childless, and practiced as an attorney. Urologic examination revealed CBAVD. Nutritional and pulmonary status were almost normal. At the age of 60 years, genetic testing indicated 2 mutations in the CFTR gene: his1282 to ter (H1282X; 602421.0129), which is associated with severe CF, and ala445 to glu (A445E; 602421.0130), which is associated with mild CF.

Animal Model

Because the pulmonary complications of CF are the most morbid aspects of the disease, a potential therapeutic strategy is to reconstitute expression of the normal CFTR gene in airway epithelia by somatic gene transfer. Engelhardt et al. (1992) developed an animal model of the human airway, using bronchial xenografts engrafted on rat tracheas and implanted into nude mice, and tested the efficiency of in vivo retroviral gene transfer. They found that in undifferentiated regenerating epithelium, 5 to 10% retroviral gene transfer was obtained, whereas in fully differentiated epithelium, no gene transfer was noted. These findings suggested that retroviral-mediated gene transfer to the airways in vivo may be feasible if the proper regenerative state can be induced.

Several groups succeeded in constructing a transgenic mouse model of cystic fibrosis (Clarke et al., 1992; Colledge et al., 1992; Dorin et al., 1992; Snouwaert et al., 1992). Unlike the HPRT-deficient mouse, constructed as a model for the Lesch-Nyhan syndrome (308000), the CFTR-deficient homozygote showed measurable defects in ion permeability of airway and intestinal epithelia, similar to those demonstrable in human CF tissues. Furthermore, most of the deficient mice had intestinal pathology similar to that of meconium ileus. Also, there appeared to be no prenatal loss from litters produced from crosses between heterozygotes. Most of the mice, however, died soon after birth as a consequence of intestinal blockage. Unlike the human male, the homozygous mouse male in at least one instance was fertile. In a transgenic mouse model of CF created by Dorin et al. (1994) through insertion in exon 10, only a low incidence of meconium ileus was observed. In contrast to the very high level of fatal intestinal obstruction in 3 other CF mouse models, they showed that the partial duplication consequent upon insertional gene targeting allowed exon skipping and aberrant splicing to produce normal Cftr mRNA, but at levels greatly reduced compared with wildtype mice. Instead of the predicted mutant Cftr transcript, a novel mRNA was produced that utilized cryptic splice sites in the disrupting plasmid sequence. Although residual wildtype mRNA in the exon 10 insertional mutant mouse seems to ameliorate the severity of the intestinal phenotype observed in the absolute 'null' CF mice, the presence of low-level residual wildtype Cftr mRNA does not correct the CF ion transport defect. The long-term survival of this insertional mutant mouse provides the opportunity to address factors important in the development of lung disease. To correct the lethal intestinal abnormalities that occur in the transgenic CFTR-null mouse, Zhou et al. (1994) used the human CFTR gene under the control of the rat intestinal fatty acid binding protein (134640) gene promoter. The mice survived and showed functional correction of ileal goblet cell and crypt cell hyperplasia and cAMP-stimulated chloride secretion. The results supported the concept that transfer of the human CFTR gene may be a useful strategy for correcting physiologic defects in patients with CF.

Mice homozygous for disruption of the Cftr gene, unlike the human disease, fail to show any gross lung pathology (Rozmahel et al. (1996)). It was proposed that a calcium-activated Cl(-) conductance could compensate for the lack of the Cftr-encoded Cl(-) channel function in these mice. The absence of this alternative chloride transport mechanism in the intestinal epithelial cells was believed to be responsible for the severe intestinal pathology observed in the same mice. Prolonged survival in these mice was demonstrated among backcross and intercross progeny with different inbred strains, suggesting that modulation of disease severity was genetically determined. A genome scan showed that the major modifier locus mapped near the centromere of mouse chromosome 7 in a region of conserved synteny with human chromosome 19q13. Candidate genes in that region include the gamma-subunit of protein kinase C (176980), the alpha-3 subunit of the type 1 Na(+)/K(+) exchanging ATPase (182350), and the sodium channel, type 1, beta-polypeptide (600235).

In connection with the design of a large-animal model for cystic fibrosis, Tebbutt et al. (1995) cloned and sequenced the CFTR cDNA of sheep. It showed a high degree of conservation at the DNA coding and predicted polypeptide levels with human CFTR; at the nucleotide level, there was a 90% conservation (compared with 80% between human and mouse). At the polypeptide level, the degree of similarity was 95% (compared with 88% between human and mouse). Northern blot analysis and reverse transcription-PCR showed that the patterns of expression of the ovine CFTR gene are very similar to those seen in humans. Further, the developmental expression of CFTR in the sheep is equivalent to that observed in humans.

Harris (1997) pointed out that the generation of cloned sheep (Campbell et al., 1996; Wilmut et al., 1997) establishes the practicality of creating an ovine model of CF. The failure of mice with disruption of the Cftr gene to reproduce the pulmonary and pancreatic features of CF may be due, in the case of the lung at least, in part to considerable differences in submucosal gland distribution in mouse and human. Mice have very few of these glands and they are restricted to the tracheal submucosa. The CFTR chloride ion channel is not expressed at high levels in the mouse pancreas, in contrast to humans where the pancreas is the site of most abundant CFTR expression. Sheep and human CFTR show greater identity and similarity than do human and mouse. Furthermore, Harris (1997) noted that the tissue-specific pattern of expression of the ovine CFTR gene and the developmental expression of CFTR in the sheep are very similar to that in humans. CF pathology commences in utero; for example, obstruction of CF pancreatic ducts by deposits of secreted material commences in the midtrimester of human gestation and by term the pancreas is structurally and functionally destroyed. Thus, in utero therapy might be necessary.

Kent et al. (1997) described the phenotype of an inbred congenic strain of CFTR-knockout mouse that developed spontaneous and progressive lung disease of early onset. The major features of the lung disease included failure of effective mucociliary transport, postbronchiolar overinflation of alveoli, and parenchymal interstitial thickening, with evidence of fibrosis and inflammatory cell recruitment. Kent et al. (1997) speculated that the basis for development of lung disease in the congenic CFTR-knockout mice is their observed lack of a non-CFTR chloride channel normally found in CFTR-knockout mice of mixed genetic background.

Using an intact human CFTR gene, Manson et al. (1997) generated transgenic mice carrying a 320-kb YAC. Mice that only expressed the human transgene were obtained by breeding with Cambridge-null CF mice. One line had approximately 2 copies of the intact YAC. Mice carrying this transgene and expressing no CFTR appeared normal and bred well, in marked contrast to the null mice, where 50% died by approximately 5 days of age. The chloride secretory responses in mice carrying the transgene were as large as or larger than those in the wildtype tissues. Expression of the transgene was highly cell-type specific and matched that of the endogenous mouse gene in the crypt epithelia throughout the gut and in salivary gland tissue. However, there was no transgene expression in some tissues, such as the Brunner glands, where it would be expected. Where there were differences between the mouse and human pattern of expression, the transgene followed the mouse pattern.

Coleman et al. (2003) found that under proper conditions, transgenic CF mice are hypersusceptible to P. aeruginosa colonization and infection and can be used for evaluation of lung pathophysiology, bacterial virulence, and development of therapies for CF lung disease.

The delta-F508 CFTR mutation results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin, a major component of the curry spice turmeric, is a nontoxic calcium-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous delta-F508 Cftr mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of delta-F508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, Egan et al. (2004) concluded that curcumin treatment may be able to correct defects associated with the homozygous expression of the delta-F508 CFTR gene, as it allows for dissociation from ER chaperone proteins and transfer to the cell membrane.

To test the hypothesis that accelerated sodium transport can produce cystic fibrosis-like lung disease, Mall et al. (2004) generated mice with airway-specific overexpression of epithelial sodium channels. Mall et al. (2004) used the airway-specific Clara cell secretory protein promoter to target expression of individual SCNN1 subunit (see 600760) transgenes to lower airway epithelia. They demonstrated that increased airway sodium absorption in vivo caused airway surface liquid volume depletion, increased mucus concentration, delayed mucus transport, and mucus adhesion to airway surfaces. Defective mucus transport caused a severe spontaneous lung disease sharing features with cystic fibrosis, including mucus obstruction, goblet cell metaplasia, neutrophilic inflammation, and poor bacterial clearance. Mall et al. (2004) concluded that increasing airway sodium absorption initiates cystic fibrosis-like lung disease and produces a model for the study of the pathogenesis and therapy of this disease.

Harmon et al. (2010) found that colonic epithelial cells and whole lung tissue from Cftr-null mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma; 601487) function that contributes to a pathologic program of gene expression. Lipidomic analysis of colonic epithelial cells suggested that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E2. Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalized the altered gene expression pattern associated with Cftr deficiency and reduced disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrase IV (CA4; 114750) and carbonic anhydrase II (CA2; 611492), increases bicarbonate secretion, and reduces mucous retention. Harmon et al. (2010) concluded that their studies revealed a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.

Rogers et al. (2008) generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The lungs of newborn CFTR-null piglets appeared normal.

Chen et al. (2010) reviewed features of the pig model of CF, which closely resembles the human disease. At birth, Cftr -/- pigs manifest pancreatic destruction, meconium ileus, early focal biliary cirrhosis, and microgallbladder. Within hours of birth, Cftr -/- pigs show reduced ability to eliminate bacteria from the lungs, but no inflammation. The inability to eliminate bacteria results in spontaneous lung disease within a few months of birth, including inflammation, infection, mucous accumulation, tissue remodeling, and airway obstruction. Chen et al. (2010) studied ion transport in newborn Cftr -/- pig nasal and tracheal/bronchial epithelia in tissues and cultures and in vivo, prior to the onset of airway inflammation. Cftr -/- epithelia showed markedly reduced Cl- and HCO3- transport, but there was no increase in transepithelial Na+ or liquid absorption or reduction in periciliary liquid depth. Like human CF, Cftr -/- pigs showed increased amiloride-sensitive voltage and current, but this was due to lack of Cl- conductance rather than increased Na+ transport.

History

Spock et al. (1967) observed that patients have a factor in serum that inhibits the action of cilia in explants of rabbit tracheal mucosa. Serum from heterozygotes contained an amount of the factor intermediate between none (the normal situation) and the level in patients.

Smith et al. (1968) found cystic fibrosis in a child with cri-du-chat syndrome (123450). Only the mother was heterozygous by Spock test. They suggested that loss of part of the short arm of the chromosome 5 derived from the father had occurred and that the deleted portion carried the cystic fibrosis locus. Danes and Bearn (1968) found vesicular metachromasia in the fibroblasts of both parents suggesting that the reported experience cannot be taken as evidence of localization of the CF gene on the short arm of chromosome 5.

Edwards et al. (1984) reported a family in which deficiency at the tip of 13q was associated with cystic fibrosis. Weak evidence supporting assignment to 13q was provided by a boy with both cystic fibrosis and hemophilia A; no translocation was visualized but the authors postulated a telomeric translocation that disrupted both loci at the tip of the X chromosome and chromosome 13. They cited 2 other observations of cystic fibrosis with chromosome 13 abnormality.

Williamson (1984) excluded cystic fibrosis from chromosome 13; none of the DNA probes that were monosomic in the case of Edwards et al. (1984) were linked to cystic fibrosis in studies of affected sibs.

In skin fibroblasts from both homozygotes and heterozygotes, Danes and Bearn (1968) found cytoplasmic intravesicular metachromasia of a type readily distinguished from that of mucopolysaccharidoses. Danes and Bearn (1969) described a morphologic change in the fibroblasts and furthermore suggested that homozygosity at either of two different loci can produce cystic fibrosis. In type I, the fibroblasts show discrete metachromatic cytoplasmic vesicles and normal mucopolysaccharide content. In type II, fibroblast metachromasia is present in both vesicles and granules and is evenly distributed through the cytoplasm; mucopolysaccharide content of the cells is markedly increased. On the basis of cell culture phenotype, Danes et al. (1978) identified 3 classes of cystic fibrosis and concluded that there is a prognostic difference between classes. They also suggested that their Class III represents the genetic compound. A deficiency of arginine esterase has been suggested by Rao and Nadler (1974), who reported absence of 1 of 3 isozymes in various cases of cystic fibrosis. Their hypothesis is that the ciliary factor and related substances are present because of failure of degradation when the enzyme is deficient. Stern et al. (1978) described a cystic fibrosis variant with little pancreatic abnormality. Hosli and Vogt (1979) claimed the successful discrimination of cystic fibrosis patients, obligatory heterozygotes (parents), and normal controls by heat inactivation of acid phosphatase and alpha-mannosidase in plasma. In this test, normals retain 80 to 100% activity, heterozygotes 40 to 60%, and CF patients almost none. There was no overlap between groups. Katznelson et al. (1983) did a stringently blinded trial of the reliability of the test of Hosli and Vogt (1979), submitting doubly coded samples to Dr. Hosli. The genotype was correctly identified in each of 45 cases. Shapiro and Lam (1982) found that the usual increase in intracellular calcium in fibroblasts with successive time (passages) in culture is exaggerated in cystic fibrosis fibroblasts. In kidney specimens obtained at autopsy from patients with cystic fibrosis, Katz et al. (1988) documented microscopic nephrocalcinosis in 35 of 38 specimens. Hypercalciuria was present in 5 of 14 patients studied. The presence of microscopic nephrocalcinosis in 3 patients less than 1 year of age suggested to these authors that the mutation in cystic fibrosis involves a primary abnormality of renal calcium metabolism. Shapiro et al. (1982) reported anomalous kinetics of mitochondrial NADH dehydrogenase in cystic fibrosis homozygotes and heterozygotes. Studying white cells, Sanguinetti-Briceno and Brock (1982) could not identify a correlation between NADH dehydrogenase and CF genotype. Shepherd et al. (1988) found that cystic fibrosis infants had 25% higher rates of total energy expenditure compared to healthy infants matched for age and body weight. The authors suggested that the data point to an energy-requiring basic defect.

REFERENCES

1.	Abeliovich, D., Lavon, I. P., Lerer, I., Cohen, T., Springer, C., Avital, A., Cutting, G. R. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. Am. J. Hum. Genet. 51: 951-956, 1992. [PubMed: 1384328, related citations] [Full Text: Pubget]

2.	Allan, J. L., Robbie, M., Phelan, P. D., Danks, D. M. Familial occurrence of meconium ileus. Europ. J. Pediat. 135: 291-292, 1981. [PubMed: 7227383, related citations] [Full Text: Pubget]

3.	Azad, A. K., Rauh, R., Vermeulen, F., Jaspers, M., Korbmacher, J., Boissier, B., Bassinet, L., Fichou, Y., des Georges, M., Stanke, F., De Boeck, K., Dupont, L., and 17 others. Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease. Hum. Mutat. 30: 1093-1103, 2009. [PubMed: 19462466, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

4.	Barreto, C., Marques Pinto, L., Duarte, A., Lavinha, J., Ramsay, M. A fertile male with cystic fibrosis: molecular genetic analysis. J. Med. Genet. 28: 420-421, 1991. [PubMed: 1870100, related citations] [Full Text: HighWire Press, Pubget]

5.	Bartlett, J. R., Friedman, K. J., Ling, S. C., Pace, R. G., Bell, S. C., Bourke, B., Castaldo, G., Castellani, C., Cipolli, M., Colombo, C., Colombo, J. L., Debray, D., and 22 others. Genetic modifiers of liver disease in cystic fibrosis. JAMA 302: 1076-1083, 2009. [PubMed: 19738092, related citations] [Full Text: HighWire Press, Pubget]

6.	Baxter, P. S., Goldhill, J., Hardcastle, J., Hardcastle, P. T., Taylor, C. J. Accounting for cystic fibrosis. (Letter) Nature 335: 211 only, 1988. [PubMed: 3412484, related citations] [Full Text: Nature Publishing Group, Pubget]

7.	Baylin, S. B., Rosenstein, B. J., Marton, L. J., Lockwood, D. H. Age-related abnormalities of circulating polyamines and diamine oxidase activity in cystic fibrosis heterozygotes and homozygotes. Pediat. Res. 14: 921-925, 1980. [PubMed: 6775274, related citations] [Full Text: Pubget]

8.	Beaudet, A., Bowcock, A., Buchwald, M., Cavalli-Sforza, L., Farrall, M., King, M.-C., Klinger, K., Lalouel, J.-M., Lathrop, G., Naylor, S., Ott, J., Tsui, L.-C., Wainwright, B., Watkins, P., White, R., Williamson, R. Linkage of cystic fibrosis to two tightly linked DNA markers: joint report from a collaborative study. Am. J. Hum. Genet. 39: 681-693, 1986. [PubMed: 3026171, related citations] [Full Text: Pubget]

9.	Beaudet, A. L., Feldman, G. L., Fernbach, S. D., Buffone, G. J., O'Brien, W. E. Linkage disequilibrium, cystic fibrosis, and genetic counseling. Am. J. Hum. Genet. 44: 319-326, 1989. [PubMed: 2916578, related citations] [Full Text: Pubget]

10.	Beaudet, A. L., Kazazian, H. H., Jr. Statement from the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis Gene. New Eng. J. Med. 323: 70-71, 1990. [PubMed: 2355964, related citations] [Full Text: Atypon, Pubget]

11.	Bilton, D., Fox, R., Webb, A. K., Lawler, W., McMahon, R. F. T., Howat, J. M. T. Pathology of common bile duct stenosis in cystic fibrosis. Gut 31: 236-238, 1990. [PubMed: 2311986, related citations] [Full Text: HighWire Press, Pubget]

12.	Bird, A. P. CpG-rich islands and the function of DNA methylation. Nature 321: 209-213, 1986. [PubMed: 2423876, related citations] [Full Text: Nature Publishing Group, Pubget]

13.	Blanck, R. R., Mendoza, E. M. Fertility in a man with cystic fibrosis. JAMA 235: 1364, 1976. [PubMed: 946259, related citations] [Full Text: Pubget]

14.	Bois, E., Feingold, J., Demenais, F., Runavot, Y., Jehanne, M., Toudic, L. Cluster of cystic fibrosis cases in a limited area of Brittany (France). Clin. Genet. 14: 73-76, 1978. [PubMed: 688690, related citations] [Full Text: Pubget]

15.	Borgo, G., Cabrini, G., Mastella, G., Ronchetto, P., Devoto, M., Romeo, G. Phenotypic intrafamilial heterogeneity in cystic fibrosis. (Letter) Clin. Genet. 44: 48-49, 1993. [PubMed: 8403455, related citations] [Full Text: Pubget]

16.	Boucher, R. C. Status of gene therapy for cystic fibrosis lung disease. J. Clin. Invest. 103: 441-445, 1999. [PubMed: 10021450, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

17.	Boue, A., Muller, F., Nezelof, C., Oury, J. F., Duchatel, F., Dumez, Y., Aubry, M. C., Boue, J. Prenatal diagnosis in 200 pregnancies with a 1-in-4 risk of cystic fibrosis. Hum. Genet. 74: 288-297, 1986. [PubMed: 3536726, related citations] [Full Text: Pubget]

18.	Bowcock, A. M., Crandall, J., Daneshvar, L., Lee, G. M., Young, B., Zunzunegui, V., Craik, C., Cavalli-Sforza, L. L., King, M.-C. Genetic analysis of cystic fibrosis: linkage of DNA and classical markers in multiplex families. Am. J. Hum. Genet. 39: 699-706, 1986. [PubMed: 3026172, related citations] [Full Text: Pubget]

19.	Boyne, J., Evans, S., Pollitt, R. J., Taylor, C. J., Dalton, A. Many delta-F508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation. (Letter) J. Med. Genet. 37: 543-547, 2000. [PubMed: 10970190, related citations] [Full Text: HighWire Press, Pubget]

20.	Bradbury, N. A., Jilling, T., Berta, G., Sorscher, E. J., Bridges, R. J., Kirk, K. L. Regulation of plasma membrane recycling by CFTR. Science 256: 530-532, 1992. [PubMed: 1373908, related citations] [Full Text: HighWire Press, Pubget]

21.	Bremer, L. A., Blackman, S. M., Vanscoy, L. L., McDougal, K. E., Bowers, A., Naughton, K. M., Cutler, D. J., Cutting, G. R. Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. Hum. Molec. Genet. 17: 2228-2237, 2008. [PubMed: 18424453, related citations] [Full Text: HighWire Press, Pubget]

22.	Breslow, J. L., Epstein, J., Fontaine, J. H., Forbes, G. B. Enhanced dexamethasone resistance in cystic fibrosis cells: potential use for heterozygote detection and prenatal diagnosis. Science 201: 180-182, 1978. [PubMed: 663650, related citations] [Full Text: HighWire Press, Pubget]

23.	Breslow, J. L., McPherson, J., Epstein, J. Distinguishing homozygous and heterozygous cystic fibrosis fibroblasts from normal cells by differences in sodium transport. New Eng. J. Med. 304: 1-5, 1981. [PubMed: 7432432, related citations] [Full Text: Atypon, Pubget]

24.	Brock, D. J. H., Gilfillan, A., Holloway, S. The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies. Clin. Genet. 53: 47-49, 1998. [PubMed: 9550361, related citations] [Full Text: Blackwell Publishing, Pubget]

25.	Brock, D. J. H., Hayward, C., Super, M. Controlled trial of serum isoelectric focusing in the detection of the cystic fibrosis gene. Hum. Genet. 60: 30-31, 1982. [PubMed: 7076245, related citations] [Full Text: Pubget]

26.	Brown, W. R., Bird, A. P. Long-range restriction site mapping of mammalian genomic DNA. Nature 322: 477-481, 1986. [PubMed: 3016554, related citations] [Full Text: Nature Publishing Group, Pubget]

27.	Brusilow, S. W. Cystic fibrosis in adults. Annu. Rev. Med. 21: 99-104, 1970. [PubMed: 4912478, related citations] [Full Text: Atypon, Pubget]

28.	Buchwald, M., Zsiga, M., Markiewicz, D., Plavsic, N., Kennedy, D., Zengerling, S., Willard, H. F., Tsipouras, P., Schmiegelow, K., Schwartz, M., Eiberg, H., Mohr, J., Barker, D., Donis-Keller, H., Tsui, L.-C. Linkage of cystic fibrosis to the pro-alpha2(I) collagen gene, COL1A2, on chromosome 7. Cytogenet. Cell Genet. 41: 234-239, 1986. [PubMed: 3011363, related citations] [Full Text: Pubget]

29.	Bullock, S., Hayward, C., Manson, J., Brock, D. J. H., Raeburn, J. A. Quantitative immunoassays for diagnosis and carrier detection in cystic fibrosis. Clin. Genet. 21: 336-341, 1982. [PubMed: 7116678, related citations] [Full Text: Pubget]

30.	Bulmer, M. G. Fibrocystic disease of the pancreas: a comment. Ann. Hum. Genet. 25: 163-164, 1961. [PubMed: 13874624, related citations] [Full Text: Pubget]

31.	Buranawuti, K., Boyle, M. P., Cheng, S., Steiner, L. L., McDougal, K., Fallin, M. D., Merlo, C., Zeitlin, P. L., Rosenstein, B. J., Mogayzel, P. J., Jr., Wang, X., Cutting, G. R. Variants in mannose-binding lectin and tumour necrosis factor alpha affect survival in cystic fibrosis. J. Med. Genet. 44: 209-214, 2007. [PubMed: 17158822, related citations] [Full Text: HighWire Press, Pubget]

32.	Campbell, K. H. S., McWhir, J., Ritchie, W. A., Wilmut, I. Sheep cloned by nuclear transfer from a cultured cell line. Nature 380: 64-66, 1996. [PubMed: 8598906, related citations] [Full Text: Nature Publishing Group, Pubget]

33.	Castellani, C., Benetazzo, M. G., Tamanini, A., Begnini, A., Mastella, G., Pignatti, P. Analysis of the entire coding region of the cystic fibrosis transmembrane regulator gene in neonatal hypertrypsinaemia with normal sweat test. (Letter) J. Med. Genet. 38: 202-205, 2001. [PubMed: 11303517, related citations] [Full Text: HighWire Press, Pubget]

34.	Cattanach, B. M., Kirk, M. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315: 496-498, 1985. [PubMed: 4000278, related citations] [Full Text: Pubget]

35.	Cavenee, W., Leach, R., Mohandas, T., Pearson, P., White, R. Isolation and regional localization of DNA segments revealing polymorphic loci from human chromosome 13. Am. J. Hum. Genet. 36: 10-24, 1984. [PubMed: 6320640, related citations] [Full Text: Pubget]

36.	Cheadle, J., Al-Jader, L., Goodchild, M., Meredith, A. L. Mild pulmonary disease in a cystic fibrosis child homozygous for R553X. J. Med. Genet. 29: 597, 1992. [PubMed: 1518030, related citations] [Full Text: HighWire Press, Pubget]

37.	Cheadle, J. P., Meredith, A. L., Al-Jader, L. N. A new missense mutation (R1283M) in exon 20 of the cystic fibrosis transmembrane conductance regulator gene. Hum. Molec. Genet. 1: 123-125, 1992. [PubMed: 1284468, related citations] [Full Text: HighWire Press, Pubget]

38.	Chen, J.-H., Stoltz, D. A., Karp, P. H., Ernst, S. E., Pezzulo, A. A., Moninger, T. O., Rector, M. V., Reznikov, L. R., Launspach, J. L., Chaloner, K., Zabner, J., Welsh, M. J. Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Cell 143: 911-923, 2010. [PubMed: 21145458, related citations] [Full Text: Elsevier Science, Pubget]

39.	Clarke, L. L., Grubb, B. R., Gabriel, S. E., Smithies, O., Koller, B. H., Boucher, R. C. Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 257: 1125-1128, 1992. [PubMed: 1380724, related citations] [Full Text: HighWire Press, Pubget]

40.	Cleghorn, G. J., Stringer, D. A., Forstner, G. G., Durie, P. R. Treatment of distal intestinal obstruction syndrome in cystic fibrosis with a balanced intestinal lavage solution. Lancet 327: 8-11, 1986. Note: Originally Volume 1. [PubMed: 2867297, related citations] [Full Text: Elsevier Science, Pubget]

41.	Cohn, J. A., Friedman, K. J., Noone, P. G., Knowles, M. R., Silverman, L. M., Jowell, P. S. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. New Eng. J. Med. 339: 653-658, 1998. [PubMed: 9725922, related citations] [Full Text: Atypon, Pubget]

42.	Coleman, F. T., Mueschenborn, S., Meluleni, G., Ray, C., Carey, V. J., Vargas, S. O., Cannon, C. L., Ausubel, F. M., Pier, G. B. Hypersusceptibility of cystic fibrosis mice to chronic Pseudomonas aeruginosa oropharyngeal colonization and lung infection. Proc. Nat. Acad. Sci. 100: 1949-1954, 2003. [PubMed: 12578988, related citations] [Full Text: HighWire Press, Pubget]

43.	Colledge, W. H., Abella, B. S., Southern, K. W., Ratcliff, R., Jiang, C., Cheng, S. H., MacVinish, L. J., Anderson, J. R., Cuthbert, A. W., Evans, M. J. Generation and characterisation of a delta-F508 cystic fibrosis mouse model. Nature Genet. 10: 445-452, 1995. [PubMed: 7545494, related citations] [Full Text: Nature Publishing Group, Pubget]

44.	Colledge, W. H., Ratcliff, R., Foster, D., Williamson, R., Evans, M. J. Cystic fibrosis mouse with intestinal obstruction. (Letter) Lancet 340: 680 only, 1992. [PubMed: 1355249, related citations] [Full Text: Pubget]

45.	Collins, A., Morton, N. E. Mapping a disease locus by allelic association. Proc. Nat. Acad. Sci. 95: 1741-1745, 1998. [PubMed: 9465087, related citations] [Full Text: HighWire Press, Pubget]

46.	Collins, F. S. Cystic fibrosis: molecular biology and therapeutic implications. Science 256: 774-779, 1992. [PubMed: 1375392, related citations] [Full Text: HighWire Press, Pubget]

47.	Colten, H. R. Screening for cystic fibrosis.(Editorial) New Eng. J. Med. 322: 328-329, 1990. [PubMed: 2296274, related citations] [Full Text: Atypon, Pubget]

48.	Corey, M., Durie, P., Moore, D., Forstner, G., Levison, H. Familial concordance of pancreatic function in cystic fibrosis. J. Pediat. 115: 274-277, 1989. [PubMed: 2754556, related citations] [Full Text: Pubget]

49.	Crystal, R. G., McElvaney, N. G., Rosenfeld, M. A., Chu, C.-S., Mastrangeli, A., Hay, J. G., Brody, S. L., Jaffe, H. A., Eissa, N. T., Danel, C. Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nature Genet. 8: 42-51, 1994. [PubMed: 7527271, related citations] [Full Text: Nature Publishing Group, Pubget]

50.	Curnow, R. N. Carrier risk calculations for recessive diseases when not all the mutant alleles are detectable. Am. J. Med. Genet. 52: 108-114, 1994. [PubMed: 7977452, related citations] [Full Text: Pubget]

51.	Curtis, A., Nelson, R., Porteous, M., Burn, J., Bhattacharya, S. S. Association of less common cystic fibrosis mutations with a mild phenotype. J. Med. Genet. 28: 34-37, 1991. [PubMed: 1999830, related citations] [Full Text: HighWire Press, Pubget]

52.	Cutting, G. R., Antonarakis, S. E., Buetow, K. H., Kasch, L. M., Rosenstein, B. J., Kazazian, H. H., Jr. Analysis of DNA polymorphism haplotypes linked to the cystic fibrosis locus in North American black and Caucasian families supports the existence of multiple mutations of the cystic fibrosis gene. Am. J. Hum. Genet. 44: 307-318, 1989. [PubMed: 2563631, related citations] [Full Text: Pubget]

53.	Cutting, G. R., Curristin, S. M., Nash, E., Rosenstein, B. J., Lerer, I., Abeliovich, D., Hill, A., Graham, C. Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians. Am. J. Hum. Genet. 50: 1185-1194, 1992. [PubMed: 1376017, related citations] [Full Text: Pubget]

54.	Danes, B. S., Bearn, A. G. Cystic fibrosis: distribution of mucopolysaccharides in fibroblast cultures. Biochem. Biophys. Res. Commun. 36: 919-924, 1969. [PubMed: 4186555, related citations] [Full Text: Elsevier Science, Pubget]

55.	Danes, B. S., Bearn, A. G. Cystic fibrosis of the pancreas. A study in cell culture. J. Exp. Med. 129: 775-794, 1969. [PubMed: 4237349, related citations] [Full Text: Pubget]

56.	Danes, B. S., Bearn, A. G. A genetic cell marker in cystic fibrosis of the pancreas. Lancet 291: 1061-1063, 1968. Note: Originally Volume 1. [PubMed: 4171744, related citations] [Full Text: Pubget]

57.	Danes, B. S., Bearn, A. G. Cystic fibrosis: an improved method for studying white blood-cells in culture. (Letter) Lancet 294: 437 only, 1969. Note: Originally Volume 2. [PubMed: 4184515, related citations] [Full Text: Pubget]

58.	Danes, B. S., Bearn, A. G. Localisation of the cystic-fibrosis gene. (Letter) Lancet 292: 1303 only, 1968. Note: Originally Volume 2. [PubMed: 4177507, related citations] [Full Text: Pubget]

59.	Danes, B. S., Beck, B., Flensborg, E. W. Cystic fibrosis: cell culture classes in a Danish population. Clin. Genet. 13: 327-334, 1978. [PubMed: 657572, related citations] [Full Text: Pubget]

60.	Danes, B. S., Hodson, M. E., Batten, J. Cystic fibrosis: evidence for a genetic compound from a family study in cell culture. Clin. Genet. 11: 83-90, 1977. [PubMed: 837566, related citations] [Full Text: Pubget]

61.	Dankert-Roelse, J. E., te Meerman, G. J. Screening for cystic fibrosis--time to change our position? (Editorial) New Eng. J. Med. 337: 997-999, 1997. [PubMed: 9309107, related citations] [Full Text: Atypon, Pubget]

62.	Danks, D. M., Allan, J., Anderson, C. M. A genetic study of fibrocystic disease of the pancreas. Ann. Hum. Genet. 28: 323-356, 1965.

63.	Danks, D. M., Allan, J., Phelan, P. D., Chapman, C. Mutations at more than one locus may be involved in cystic fibrosis--evidence based on first-cousin data and direct counting of cases. Am. J. Hum. Genet. 35: 838-844, 1983. Note: Retraction: Am. J. Hum. Genet. 36: 1401-1402, 1984. [PubMed: 6351603, related citations] [Full Text: Pubget]

64.	Davies, J., Neth, O., Alton, E., Klein, N., Turner, M. Differential binding of mannose-binding lectin to respiratory pathogens in cystic fibrosis. Lancet 355: 1885-1886, 2000. [PubMed: 10866448, related citations] [Full Text: Elsevier Science, Pubget]

65.	Dean, M. Resolving DNA mutations. Nature Genet. 9: 103-104, 1995. [PubMed: 7719330, related citations] [Full Text: Nature Publishing Group, Pubget]

66.	de Becdelievre, A., Costa, C., Jouannic, J.-M., LeFloch, A., Giurgea, I., Martin, J., Medina, R., Boissier, B., Gameiro, C., Muller, F., Goossens, M., Alberti, C., Girodon, E. Comprehensive description of CFTR genotypes and ultrasound patterns in 694 cases of fetal bowel anomalies: a revised strategy. Hum. Genet. 129: 387-396, 2011. [PubMed: 21184098, related citations] [Full Text: Springer, Pubget]

67.	Dequeker, E., Stuhrmann, M., Morris, M. A., Casals, T., Castellani, C., Claustres, M., Cuppens, H., des Georges, M., Ferec, C., Macek, M., Pignatti, P.-F., Scheffer, H., Schwartz, M., Witt, M., Schwarz, M., Girodon, E. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations. Europ. J. Hum. Genet. 17: 51-65, 2009. [PubMed: 18685558, related citations] [Full Text: Nature Publishing Group, Pubget]

68.	De Rose, V., Arduino, C., Cappello, N., Piana, R., Salmin, P., Bardessono, M., Goia, M., Padoan, R., Bignamini, E., Costantini, D., Pizzamiglio, G., Bennato, V., Colombo, C., Giunta, A., Piazza, A. Fc-gamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis. Europ. J. Hum. Genet. 13: 96-101, 2005. [PubMed: 15367919, related citations] [Full Text: Nature Publishing Group, Pubget]

69.	Devoto, M., De Benedetti, L., Seia, M., Piceni Sereni, L., Ferrari, M., Bonduelle, M. L., Malfroot, A., Lissens, W., Balassopoulou, A., Adam, G., Loukopoulos, D., Cochaux, P., Vassart, G., Szibor, R., Hein, J., Grade, K., Berger, W., Wainwright, B., Romeo, G. Haplotypes in cystic fibrosis patients with or without pancreatic insufficiency from four European populations. Genomics 5: 894-898, 1989. [PubMed: 2574150, related citations] [Full Text: Pubget]

70.	Devoto, M., Ronchetto, P., Fanen, P., Orriols, J. J. T., Romeo, G., Goossens, M., Ferrari, M., Magnani, C., Seia, M., Cremonesi, L. Screening for non-delta-F508 mutations in five exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in Italy. Am. J. Hum. Genet. 48: 1127-1132, 1991. [PubMed: 1709778, related citations] [Full Text: Pubget]

71.	de Vries, H. G., Collee, J. M., de Walle, H. E. K., van Veldhuizen, M. H. R., Smit Sibinga, C. T., Scheffer, H., ten Kate, L. P. Prevalence of delta-F508 cystic fibrosis carriers in The Netherlands: logistic regression on sex, age, region of residence and number of offspring. Hum. Genet. 99: 74-79, 1997. [PubMed: 9003498, related citations] [Full Text: Springer, Pubget]

72.	Di Sant'Agnese, P. A., Davis, P. B. Cystic fibrosis in adults: 75 cases and a review of 232 cases in the literature. Am. J. Med. 66: 121-132, 1979. [PubMed: 420238, related citations] [Full Text: Pubget]

73.	Di Sant'Agnese, P. A., Davis, P. B. Research in cystic fibrosis. New Eng. J. Med. 295: 481-485, and 534-541, and 597-602, 1976. [PubMed: 781537, related citations] [Full Text: Atypon, Pubget]

74.	Di Sant'Agnese, P. A., Talamo, R. C. Pathogenesis and physiopathology of cystic fibrosis of the pancreas: fibrocystic disease of the pancreas (muco-viscidosis). New Eng. J. Med. 277: 1287-1294 and 1344-1352, 1967. [PubMed: 4864201, related citations] [Full Text: Atypon, Pubget]

75.	Dorfman, R., Sandford, A., Taylor, C., Huang, B., Frangolias, D., Wang, Y., Sang, R., Pereira, L., Sun, L., Berthiaume, Y., Tsue, L.-C., Pare, P. D., Durie, P., Corey, M., Zielenski, J. Complex two-gene modulation of lung disease severity in children with cystic fibrosis. J. Clin. Invest. 118: 1040-1049, 2008. [PubMed: 18292811, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

76.	Dorin, J. R., Dickinson, P., Alton, E. W. F. W., Smith, S. N., Geddes, D. M., Stevenson, B. J., Kimber, W. L., Fleming, S., Clarke, A. R., Hooper, M. L., Anderson, L., Beddington, R. S. P., Porteous, D. J. Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 359: 211-215, 1992. [PubMed: 1382232, related citations] [Full Text: Nature Publishing Group, Pubget]

77.	Dorin, J. R., Stevenson, B. J., Fleming, S., Alton, E. W. F. W., Dickinson, P., Porteous, D. J. Long-term survival of the exon 10 insertional cystic fibrosis mutant mouse is a consequence of low level residual wild-type Cftr gene expression. Mammalian Genome 5: 465-472, 1994. [PubMed: 7949729, related citations] [Full Text: Pubget]

78.	Dork, T., El-Harith, E.-H. A., Stuhrmann, M., Macek, M., Jr., Egan, M., Cutting, G. R., Tzetis, M., Kanavakis, E., Carles, S., Claustres, M., Padoa, C., Ramsay, M., Schmidtke, J. Evidence for a common ethnic origin of cystic fibrosis mutation 3120+1G-to-A in diverse populations. (Letter) Am. J. Hum. Genet. 63: 656-662, 1998. [PubMed: 9683582, related citations] [Full Text: Elsevier Science, Pubget]

79.	Dork, T., Wulbrand, U., Richter, T., Neumann, T., Wolfes, H., Wulf, B., Maass, G., Tummler, B. Cystic fibrosis with three mutations in the cystic fibrosis transmembrane conductance regulator gene. Hum. Genet. 87: 441-446, 1991. [PubMed: 1715308, related citations] [Full Text: Pubget]

80.	Drumm, M. L., Konstan, M. W., Schluchter, M. D., Handler, A., Pace, R., Zou, F., Zariwala, M., Fargo, D., Xu, A., Dunn, J. M., Darrah, R. J., and 9 others. Genetic modifiers of lung disease in cystic fibrosis. New Eng. J. Med. 353: 1443-1453, 2005. [PubMed: 16207846, related citations] [Full Text: Atypon, Pubget]

81.	Dumur, V., Lafitte, J. J., Gervais, R., Debaecker, D., Kesteloot, M., Lalau, G., Roussel, P. Abnormal distribution of cystic fibrosis delta-F508 allele in adults with chronic bronchial hypersecretion. Lancet 335: 1340, 1990. [PubMed: 1971393, related citations] [Full Text: Elsevier Science, Pubget]

82.	Duncan, A. M. V., Buchwald, M., Tsui, L.-C. In situ hybridization of two cloned chromosome 7 sequences tightly linked to the cystic fibrosis locus. Cytogenet. Cell Genet. 49: 309-310, 1988. [PubMed: 3248389, related citations] [Full Text: Pubget]

83.	Edwards, J. H., Jonasson, J. A., Blackwell, N. L. Locus for cystic fibrosis. (Letter) Lancet 323: 1020 only, 1984. Note: Originally Volume 1. [PubMed: 6143942, related citations] [Full Text: Pubget]

84.	Edwards, J. H., Miciak, A. The slash sheet: a simple procedure for risk analysis in cystic fibrosis. (Letter) Am. J. Hum. Genet. 47: 1024-1028, 1990. [PubMed: 2239967, related citations] [Full Text: Pubget]

85.	Egan, M. E., Pearson, M., Weiner, S. A., Rajendran, V., Rubin, D., Glockner-Pagel, J., Canny, S., Du, K., Lukacs, G. L., Caplan, M. J. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 304: 600-602, 2004. [PubMed: 15105504, related citations] [Full Text: HighWire Press, Pubget]

86.	Eiberg, H., Mohr, J., Nielsen, L. S. Linkage relationships of human coagulation factor XIIIB. (Abstract) Cytogenet. Cell Genet. 37: 463 only, 1984.

87.	Eiberg, H., Mohr, J., Schmiegelow, K., Nielsen, L. S., Williamson, R. Linkage relationships of paraoxonase (PON) with other markers: indication of PON-cystic fibrosis synteny. Clin. Genet. 28: 265-271, 1985. [PubMed: 2998653, related citations] [Full Text: Pubget]

88.	Eiberg, H., Schmiegelow, K., Koch, C., Mohr, J., Schwartz, M., Niebuhr, E. Cystic fibrosis; hint of linkage with F13B. Clin. Genet. 27: 206, 1985. [PubMed: 3856494, related citations] [Full Text: Pubget]

89.	Eiberg, H., Schmiegelow, K., Tsui, L.-C., Buchwald, M., Niebuhr, E., Phelan, P. D., Williamson, R., Warwick, W., Koch, C., Mohr, J. Cystic fibrosis, linkage with PON. (Abstract) Cytogenet. Cell Genet. 40: 623, 1985.

90.	El-Harith, E.-H. A., Stuhrmann, M., Dork, T., Eskandarani, H. A., Schmidtke, J. PCR-based analysis of cystic fibrosis mutations specific for Saudi patients. Saudi Med. J. 19: 148-152, 1998.

91.	Engel, E. A new genetic concept: uniparental disomy and its potential effect, isodisomy. Am. J. Med. Genet. 6: 137-143, 1980. [PubMed: 7192492, related citations] [Full Text: Pubget]

92.	Engelhardt, J. F., Yankaskas, J. R., Wilson, J. M. In vivo retroviral gene transfer into human bronchial epithelia of xenografts. J. Clin. Invest. 90: 2598-2607, 1992. [PubMed: 1281842, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

93.	Ernst, R. K., Yi, E. C., Guo, L., Lim, K. B., Burns, J. L., Hackett, M., Miller, S. I. Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa. Science 286: 1561-1565, 1999. [PubMed: 10567263, related citations] [Full Text: HighWire Press, Pubget]

94.	Estivill, X., Chillon, M., Casals, T., Bosch, A., Morral, N., Nunes, V., Gasparini, P., Seia, A., Pignatti, P. F., Novelli, G., Dallapiccola, B., Fernandez, E., Benitez, J., Williamson, R. Delta-F508 gene deletion in cystic fibrosis in Southern Europe. (Letter) Lancet 334: 1404-1405, 1989. Note: Originally Volume 2. [PubMed: 2574355, related citations] [Full Text: Pubget]

95.	Estivill, X., Farrall, M., Scambler, P. J., Bell, G. M., Hawley, K. M. F., Lench, N. J., Bates, G. P., Kruyer, H. C., Frederick, P. A., Stanier, P., Watson, E. K., Williamson, R., Wainwright, B. J. A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands. Nature 326: 840-845, 1987. [PubMed: 2883581, related citations] [Full Text: Nature Publishing Group, Pubget]

96.	Estivill, X., Farrall, M., Williamson, R., Ferrari, M., Seia, M., Giunta, A. M., Novelli, G., Potenza, L., Dallapicolla, B., Borgo, G., Gasparini, P., Pignatti, P. F., De Benedetti, L., Vitale, E., Devoto, M., Romeo, G. Linkage disequilibrium between cystic fibrosis and linked DNA polymorphisms in Italian families: a collaborative study. Am. J. Hum. Genet. 43: 23-28, 1988. [PubMed: 2897786, related citations] [Full Text: Pubget]

97.	European Working Group on CF Genetics. Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. Hum. Genet. 85: 436-445, 1990. [PubMed: 2210767, related citations] [Full Text: Pubget]

98.	Fajac, I., Viel, M., Sublemontier, S., Hubert, D., Bienvenu, T. Could a defective epithelial sodium channel lead to bronchiectasis. Respir. Res. 9: 46, 2008. Note: Electronic Article. [PubMed: 18507830, related citations] [Full Text: BioMed Central, Pubget]

99.	Fanen, P., Ghanem, N., Vidaud, M., Besmond, C., Martin, J., Costes, B., Plassa, F., Goossens, M. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics 13: 770-776, 1992. [PubMed: 1379210, related citations] [Full Text: Elsevier Science, Pubget]

100.	Farrall, M., Law, H.-Y., Rodeck, C. H., Warren, R., Stanier, P., Super, M., Lissens, W., Scambler, P., Watson, E., Wainwright, B., Williamson, R. First-trimester prenatal diagnosis of cystic fibrosis with linked DNA probes. Lancet 327: 1402-1405, 1986. Note: Originally Volume 1. [PubMed: 2872515, related citations] [Full Text: Pubget]

101.	Farrall, M., Scambler, P., Klinger, K. W., Davies, K., Worrall, C., Williamson, R., Wainwright, B. Cystic fibrosis carrier detection using a linked gene probe. J. Med. Genet. 23: 295-299, 1986. [PubMed: 3018247, related citations] [Full Text: HighWire Press, Pubget]

102.	Farrall, M., Scambler, P., North, P., Williamson, R. The analysis of multiple polymorphic loci on a single human chromosome to exclude linkage to inherited disease: cystic fibrosis and chromosome 4. Am. J. Hum. Genet. 38: 75-83, 1986. [PubMed: 3004205, related citations] [Full Text: Pubget]

103.	Farrall, M., Watson, E., Bates, G., Bell, G., Bell, J., Davies, K. A., Estivill, X., Kruyer, H., Law, H.-Y., Lench, N., Lissens, W., Simon, P., Scambler, P., Stanier, P., Vassart, G., Worrall, C., Williamson, R., Wainwright, B. J. Further data supporting linkage between cystic fibrosis and the met oncogene and haplotype analysis with met and pJ3.11. Am. J. Hum. Genet. 39: 713-719, 1986. [PubMed: 3467586, related citations] [Full Text: Pubget]

104.	Farrell, P. M., Kosorok, M. R., Laxova, A., Shen, G., Koscik, R. E., Bruns, W. T., Splaingard, M., Mischler, E. H. Nutritional benefits of neonatal screening for cystic fibrosis. New Eng. J. Med. 337: 963-969, 1997. [PubMed: 9395429, related citations] [Full Text: Atypon, Pubget]

105.	Farrell, P. M., Kosorok, M. R., Rock, M. J., Laxova, A., Zeng, L., Lai, H.-C., Hoffman, G., Laessig, R. H., Splaingard, M. L., Wisconsin Cystic Fibrosis Neonatal Screening Study Group. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 107: 1-12, 2001. [PubMed: 11134427, related citations] [Full Text: HighWire Press, Pubget]

106.	Ferec, C., Audrezet, M. P., Mercier, B., Guillermit, H., Moullier, P., Quere, I., Verlingue, C. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nature Genet. 1: 188-191, 1992. [PubMed: 1284639, related citations] [Full Text: Nature Publishing Group, Pubget]

107.	Ferrari, M., Antonelli, M., Bellini, F., Borgo, G., Castiglione, O., Curcio, L., Dallapiccola, B., Devoto, M., Estivill, X., Gasparini, P., Giunta, A., Marianelli, L., Mastella, G., Novelli, G., Pignatti, P., Romano, L., Romeo, G., Seia, M., Williamson, R. Genetic differences in cystic fibrosis patients with and without pancreatic insufficiency: an Italian collaborative study. Hum. Genet. 84: 435-438, 1990. [PubMed: 2323776, related citations] [Full Text: Pubget]

108.	FitzSimmons, S. C., Burkhart, G. A., Borowitz, D., Grand, R. J., Hammerstrom, T., Durie, P. R., Lloyd-Still, J. D., Lowenfels, A. B. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New Eng. J. Med. 336: 1283-1289, 1997. [PubMed: 9113931, related citations] [Full Text: Atypon, Pubget]

109.	Freedman, S. D., Blanco, P. G., Zaman, M. M., Shea, J. C., Ollero, M., Hopper, I. K., Weed, D. A., Gelrud, A., Regan, M. M., Laposata, M., Alvarez, J. G., O'Sullivan, B. P. Association of cystic fibrosis with abnormalities in fatty acid metabolism. New Eng. J. Med. 350: 560-569, 2004. [PubMed: 14762183, related citations] [Full Text: Atypon, Pubget]

110.	Frizzell, R. A. Cystic fibrosis: a disease of ion channels? Trends Neurosci. 10: 190-193, 1987.

111.	Frydman, M. I. Epidemiology of cystic fibrosis: a review. J. Chronic Dis. 32: 211-219, 1979. [PubMed: 372201, related citations] [Full Text: Pubget]

112.	Fujiwara, T. M., Morgan, K., Schwartz, R. H., Doherty, R. A., Miller, S. R., Klinger, K., Stanislovitis, P., Stuart, N., Watkins, P. C. Genealogical analysis of cystic fibrosis families and chromosome 7q RFLP haplotypes in the Hutterite brethren. Am. J. Hum. Genet. 44: 327-337, 1989. [PubMed: 2563632, related citations] [Full Text: Pubget]

113.	Gabolde, M., Hubert, D., Guilloud-Bataille, M., Lenaerts, C., Feingold, J., Besmond, C. The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis. J. Med. Genet. 38: 310-311, 2001. [PubMed: 11333866, related citations] [Full Text: HighWire Press, Pubget]

114.	Gabriel, S. E., Brigman, K. N., Koller, B. H., Boucher, R. C., Stutts, M. J. Cystic fibrosis heterozygote resistance to cholera toxin in cystic fibrosis mouse model. Science 266: 107-109, 1994. [PubMed: 7524148, related citations] [Full Text: HighWire Press, Pubget]

115.	Garred, P., Pressler, T., Madsen, H. O., Frederiksen, B., Svejgaard, A., Hoiby, N., Schwartz, M., Koch, C. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J. Clin. Invest. 104: 431-437, 1999. [PubMed: 10449435, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

116.	Gaskin, K. J., Waters, D. L. M., Howman-Giles, R., de Silva, M., Earl, J. W., Martin, H. C. O., Kan, A. E., Brown, J. M., Dorney, S. F. A. Liver disease and common-bile-duct stenosis in cystic fibrosis. New Eng. J. Med. 318: 340-346, 1988. [PubMed: 3340104, related citations] [Full Text: Atypon, Pubget]

117.	Gasparini, P., Novelli, G., Estivill, X., Olivieri, D., Savoia, A., Ruzzo, A., Nunes, V., Borgo, G., Antonelli, M., Williamson, R., Pignatti, P. F., Dallapiccola, B. The genotype of a new linked DNA marker, MP6d-9, is related to the clinical course of cystic fibrosis. J. Med. Genet. 27: 17-20, 1990. [PubMed: 1968514, related citations] [Full Text: HighWire Press, Pubget]

118.	Goodchild, M. C., Edwards, J. H., Glenn, K. P., Grindey, C., Harris, R., Mackintosh, P., Wentzel, L. A search for linkage in cystic fibrosis. J. Med. Genet. 13: 417-419, 1976. [PubMed: 1018300, related citations] [Full Text: HighWire Press, Pubget]

119.	Groman, J. D., Meyer, M. E., Wilmott, R. W., Zeitlin, P. L., Cutting, G. R. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. New Eng. J. Med. 347: 401-407, 2002. [PubMed: 12167682, related citations] [Full Text: Atypon, Pubget]

120.	Gu, Y., Harley, I. T. W., Henderson, L. B., Aronow, B. J., Vietor, I., Huber, L. A., Harley, J. B., Kilpatrick, J. R., Langefeld, C. D., Williams, A. H., Jegga, A. G., Chen, J., and 11 others. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 458: 1039-1042, 2009. [PubMed: 19242412, related citations] [Full Text: Nature Publishing Group, Pubget]

121.	Hammond, K. B., Abman, S. H., Sokol, R. J., Accurso, F. J. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. New Eng. J. Med. 325: 769-774, 1991. [PubMed: 1870650, related citations] [Full Text: Atypon, Pubget]

122.	Handyside, A. H., Lesko, J. G., Tarin, J. J., Winston, R. M. L., Hughes, M. R. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. New Eng. J. Med. 327: 905-909, 1992. [PubMed: 1381054, related citations] [Full Text: Atypon, Pubget]

123.	Hansson, G. C. Cystic fibrosis and chloride-secreting diarrhoea. (Letter) Nature 333: 711, 1988. [PubMed: 2455229, related citations] [Full Text: Nature Publishing Group, Pubget]

124.	Hardin, D. S., Adams-Huet, B., Brown, D., Chatfield, B., Dyson, M., Ferkol, T., Howenstine, M., Prestidge, C., Royce, F., Rice, J., Seilheimer, D. K., Steelman, J., Shepherds, R. Growth hormone treatment improves growth and clinical status in prepubertal children with cystic fibrosis: results of a multicenter randomized controlled trial. J. Clin. Endocr. Metab. 91: 4925-4929, 2006. [PubMed: 17018651, related citations] [Full Text: HighWire Press, Pubget]

125.	Harmon, G. S., Dumlao, D. S., Ng, D. T., Barrett, K. E., Dennis, E. A., Dong, H., Glass, C. K. Pharmacological correction of a defect in PPAR-gamma signaling ameliorates disease severity in Cftr-deficient mice. Nature Med. 16: 313-318, 2010. [PubMed: 20154695, related citations] [Full Text: Nature Publishing Group, Pubget]

126.	Harris, A. Towards an ovine model of cystic fibrosis. Hum. Molec. Genet. 6: 2191-2193, 1997. [PubMed: 9361022, related citations] [Full Text: HighWire Press, Pubget]

127.	Harris, A., Quinlan, C., Bobrow, M. Cystic fibrosis typing with DNA probes: experience of a screening laboratory. Hum. Genet. 79: 76-79, 1988. [PubMed: 2896624, related citations] [Full Text: Pubget]

128.	Harris, R. L., Riley, H. D., Jr. Cystic fibrosis in the American Indian. Pediatrics 41: 733-738, 1968. [PubMed: 5643981, related citations] [Full Text: Pubget]

129.	Hill, A. J. M., Graham, C. A., Kelly, E. D., Morrison, P. J., Nevin, N. C. Linkage disequilibrium and CF allele segregation analysis in cystic fibrosis families in Northern Ireland. Hum. Genet. 83: 391-394, 1989. [PubMed: 2572538, related citations] [Full Text: Pubget]

130.	Hodge, S. E., Lebo, R. V., Yesley, A. R., Cheney, S. M., Angle, H., Milunsky, J. Calculating posterior cystic fibrosis risk with echogenic bowel and one characterized cystic fibrosis mutation: avoiding pitfalls in the risk calculations. Am. J. Med. Genet. 82: 329-335, 1999. [PubMed: 10051167, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

131.	Hogenauer, C., Santa Ana, C. A., Porter, J. L., Millard, M., Gelfand, A., Rosenblatt, R. L., Prestidge, C. B., Fordtran, J. S. Active intestinal chloride secretion in human carriers of cystic fibrosis mutations: an evaluation of the hypothesis that heterozygotes have subnormal active intestinal chloride secretion. Am. J. Hum. Genet. 67: 1422-1427, 2000. [PubMed: 11055897, related citations] [Full Text: Elsevier Science, Pubget]

132.	Honeyman, M. S., Siker, E. Cystic fibrosis of the pancreas: an estimate of the incidence. Am. J. Hum. Genet. 17: 461-465, 1965. [PubMed: 5844121, related citations] [Full Text: Pubget]

133.	Horn, S. D., Horn, R. A., Sharkey, P. D., Beall, R. J., Hoff, J. S., Rosenstein, B. J. Misclassification problems in diagnosis-related groups: cystic fibrosis as an example. New Eng. J. Med. 314: 484-487, 1986. [PubMed: 3080680, related citations] [Full Text: Atypon, Pubget]

134.	Hosli, P., Vogt, E. Detection of cystic fibrosis homozygotes and heterozygotes with plasma. Lancet 314: 543-546, 1979. Note: Originally Volume 1.

135.	Hubbard, R. C., McElvaney, N. G., Birrer, P., Shak, S., Robinson, W. W., Jolley, C., Wu, M., Chernick, M. S., Crystal, R. G. A preliminary study of aerosolized recombinant human deoxyribonuclease I in the treatment of cystic fibrosis. New Eng. J. Med. 326: 812-815, 1992. [PubMed: 1538726, related citations] [Full Text: Atypon, Pubget]

136.	Hyde, S. C., Gill, D. R., Higgins, C. F., Trezise, A. E. O., MacVinish, L. J., Cuthbert, A. W., Ratcliff, R., Evans, M. J., Colledge, W. H. Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature 362: 250-255, 1993. [PubMed: 7681548, related citations] [Full Text: Nature Publishing Group, Pubget]

137.	Jetten, A. M., Yankaskas, J. R., Stutts, M. J., Willumsen, N. J., Boucher, R. C. Persistence of abnormal chloride conductance regulation in transformed cystic fibrosis epithelia. Science 244: 1472-1475, 1989. [PubMed: 2472008, related citations] [Full Text: HighWire Press, Pubget]

138.	Johannesson, M., Gottlieb, C., Hjelte, L. Delayed puberty in girls with cystic fibrosis despite good clinical status. Pediatrics 99: 29-34, 1997. [PubMed: 8989333, related citations] [Full Text: HighWire Press, Pubget]

139.	Jorde, L. B., Lathrop, G. M. A test of the heterozygote-advantage hypothesis in cystic fibrosis carriers. Am. J. Hum. Genet. 42: 808-815, 1988. [PubMed: 3369446, related citations] [Full Text: Pubget]

140.	Kabra, M, Kabra, S. K., Ghosh, M., Khanna, A., Arora, S., Menon, P. S. N., Verma, I. C. Is the spectrum of mutations in Indian patients with cystic fibrosis different? (Letter) Am. J. Med. Genet. 93: 161-163, 2000. [PubMed: 10869121, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

141.	Katz, S. M., Krueger, L. J., Falkner, B. Microscopic nephrocalcinosis in cystic fibrosis. New Eng. J. Med. 319: 263-266, 1988. [PubMed: 3393180, related citations] [Full Text: Atypon, Pubget]

142.	Katznelson, D., Ben-Yishay, M. Cystic fibrosis in Israel: clinical and genetic aspects. Isr. J. Med. Sci. 14: 204-211, 1978. [PubMed: 649347, related citations] [Full Text: Pubget]

143.	Katznelson, D., Blau, H., Sack, J. Detection of cystic-fibrosis genotypes. (Letter) Lancet 322: 622 only, 1983. Note: Originally Volume 1.

144.	Kent, G., Iles, R., Bear, C. E., Huan, L.-J., Griesenbach, U., McKerlie, C., Frndova, H., Ackerley, C., Gosselin, D., Radzioch, D., O'Brodovich, H., Tsui, L.-C., Buchwald, M., Tanswell, A. K. Lung disease in mice with cystic fibrosis. J. Clin. Invest. 100: 3060-3069, 1997. [PubMed: 9399953, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

145.	Kerem, B., Buchanan, J. A., Durie, P., Corey, M. L., Levison, H., Rommens, J. M., Buchwald, M., Tsui, L.-C. DNA marker haplotype association with pancreatic sufficiency in cystic fibrosis. Am. J. Hum. Genet. 44: 827-834, 1989. [PubMed: 2567116, related citations] [Full Text: Pubget]

146.	Kerem, B., Rommens, J. M., Buchanan, J. A., Markiewicz, D., Cox, T. K., Chakravarti, A., Buchwald, M., Tsui, L.-C. Identification of the cystic fibrosis gene: genetic analysis. Science 245: 1073-1080, 1989. [PubMed: 2570460, related citations] [Full Text: HighWire Press, Pubget]

147.	Kerem, E., Kalman, Y. M., Yahav, Y., Shoshani, T., Abeliovich, D., Szeinberg, A., Rivlin, J., Blau, H., Tal, A., Ben-Tur, L., Springer, C., Augarten, A., Godfrey, S., Lerer, I., Branski, D., Friedman, M., Kerem, B. Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel. Hum. Genet. 96: 193-197, 1995. [PubMed: 7635469, related citations] [Full Text: Pubget]

148.	Klinger, K., Horn, G. T., Stanislovitis, P., Schwartz, R. H., Fujiwara, T. M., Morgan, K. Cystic fibrosis mutations in the Hutterite brethren. Am. J. Hum. Genet. 46: 983-987, 1990. [PubMed: 2339696, related citations] [Full Text: Pubget]

149.	Klinger, K., Stanislovitis, P., Hoffman, N., Watkins, P. C., Schwartz, R., Doherty, R., Scambler, P., Farrall, M., Williamson, R., Wainwright, B. Genetic homogeneity of cystic fibrosis. Nucleic Acids Res. 14: 8681-8686, 1986. [PubMed: 3786136, related citations] [Full Text: HighWire Press, Pubget]

150.	Klinger, K. W. Cystic fibrosis in the Ohio Amish: gene frequency and founder effect. Hum. Genet. 65: 94-98, 1983. [PubMed: 6654341, related citations] [Full Text: Pubget]

151.	Knowles, M., Gatzy, J., Boucher, R. Relative ion permeability of normal and cystic fibrosis nasal epithelium. J. Clin. Invest. 71: 1410-1417, 1983. [PubMed: 6853720, related citations] [Full Text: Pubget]

152.	Knowles, M. R., Barnett, T. B., McConkie-Rosell, A., Sawyer, C., Kahler, S. G. Mild cystic fibrosis in a consanguineous family. Ann. Intern. Med. 110: 599-605, 1989. [PubMed: 2930093, related citations] [Full Text: Pubget]

153.	Knowles, M. R., Hohneker, K. W., Zhou, Z., Olsen, J. C., Noah, T. L., Hu, P.-C., Leigh, M. W., Engelhardt, J. F., Edwards, L. J., Jones, K. R., Grossman, M., Wilson, J. M., Johnson, L. G., Boucher, R. C. A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. New Eng. J. Med. 333: 823-831, 1995. [PubMed: 7544439, related citations] [Full Text: Atypon, Pubget]

154.	Knowlton, R. G., Cohen-Haguenauer, O., Van Cong, N., Frezal, J., Brown, V. A., Barker, D., Braman, J. C., Schumm, J. W., Tsui, L.-C., Buchwald, M., Donis-Keller, H. A polymorphic DNA marker linked to cystic fibrosis is located on chromosome 7. Nature 318: 380-382, 1985. [PubMed: 2999611, related citations] [Full Text: Pubget]

155.	Kravchenko, V. V., Kaufmann, G. F., Mathison, J. C., Scott, D. A., Katz, A. Z., Grauer, D. C., Lehmann, M., Meijler, M. M., Janda, K. D., Ulevitch, R. J. Modulation of gene expression via disruption of NF-kappa-B signaling by a bacterial small molecule. Science 321: 259-263, 2008. [PubMed: 18566250, related citations] [Full Text: HighWire Press, Pubget]

156.	Krawczak, M., Konecki, D. S., Schmidtke, J., Duck, M., Engel, W., Nutzenadel, W., Trefz, F. K. Allelic association of the cystic fibrosis locus and two DNA markers, XV2c and KM19, in 55 German families. Hum. Genet. 80: 78-80, 1988. [PubMed: 2901397, related citations] [Full Text: Pubget]

157.	Kristidis, P., Bozon, D., Corey, M., Markiewicz, D., Rommens, J., Tsui, L.-C., Durie, P. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am. J. Hum. Genet. 50: 1178-1184, 1992. [PubMed: 1376016, related citations] [Full Text: Pubget]

158.	Kubesch, P., Dork, T., Wulbrand, U., Kalin, N., Neumann, T., Wulf, B., Geerlings, H., Weissbrodt, H., von der Hardt, H., Tummler, B. Genetic determinants of airways' colonisation with Pseudomonas aeruginosa in cystic fibrosis. Lancet 341: 189-193, 1993. [PubMed: 7678316, related citations] [Full Text: Elsevier Science, Pubget]

159.	Kulczycki, L. L., Kostuch, M., Bellanti, J. A. A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations. Am. J. Med. Genet. 116A: 262-267, 2003. [PubMed: 12503104, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

160.	Lander, E. S., Botstein, D. Consanguinity and heterogeneity: cystic fibrosis need not be homogeneous in Italy. (Letter) Am. J. Hum. Genet. 39: 282-283, 1986. [PubMed: 3752091, related citations] [Full Text: Pubget]

161.	Landry, D. W., Akabas, M. H., Redhead, C., Edelman, A., Cragoe, E. J., Jr., Al-Awqati, Q. Purification and reconstitution of chloride channels from kidney and trachea. Science 244: 1469-1472, 1989. [PubMed: 2472007, related citations] [Full Text: HighWire Press, Pubget]

162.	Laroche, D., Travert, G. Abnormal frequency of delta-F(508) mutation in neonatal transitory hypertrypsinaemia. (Letter) Lancet 337: 55 only, 1991. [PubMed: 1670678, related citations] [Full Text: Elsevier Science, Pubget]

163.	Lemna, W. K., Feldman, G. L., Kerem, B., Fernbach, S. D., Zevkovich, E. P., O'Brien, W. E., Riordan, J. R., Collins, F. S., Tsui, L.-C., Beaudet, A. L. Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis. New Eng. J. Med. 322: 291-296, 1990. [PubMed: 2296270, related citations] [Full Text: Atypon, Pubget]

164.	Levitan, I. B. The basic defect in cystic fibrosis. Science 244: 1423, 1989. [PubMed: 2544028, related citations] [Full Text: HighWire Press, Pubget]

165.	Lowe, C. U., May, C. D., Reed, S. C. Fibrosis of the pancreas in infants and children: a statistical study of clinical and hereditary features. Am. J. Dis. Child. 78: 349-374, 1949. [PubMed: 18138931, related citations] [Full Text: HighWire Press, Pubget]

166.	Macek, M., Jr., Mackova, A., Hamosh, A., Hilman, B. C., Selden, R. F., Lucotte, G., Friedman, K. J., Knowles, M. R., Rosenstein, B. J., Cutting, G. R. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am. J. Hum. Genet. 60: 1122-1127, 1997. [PubMed: 9150159, related citations] [Full Text: Pubget]

167.	Mall, M., Grubb, B. R., Harkema, J. R., O'Neal, W. K., Boucher, R. C. Increased airway epithelial Na(+) absorption produces cystic fibrosis-like lung disease in mice. Nature Med. 10: 487-493, 2004. [PubMed: 15077107, related citations] [Full Text: Nature Publishing Group, Pubget]

168.	Mangos, J. A., McSherry, N. R. Studies on the mechanism of inhibition of sodium transport in cystic fibrosis of the pancreas. Pediat. Res. 2: 378-384, 1968. [PubMed: 5672699, related citations] [Full Text: Pubget]

169.	Manson, A. L., Trezise, A. E. O., MacVinish, L. J., Kasschau, K. D., Birchall, N., Episkopou, V., Vassaux, G., Evans, M. J., Colledge, W. H., Cuthbert, A. W., Huxley, C. Complementation of null CF mice with a human CFTR YAC transgene. EMBO J. 16: 4238-4249, 1997. [PubMed: 9250667, related citations] [Full Text: Pubget]

170.	Manson, J. C., Brock, D. J. H. Development of a quantitative immunoassay for the cystic fibrosis gene. Lancet 315: 330-331, 1980. Note: Originally Volume 1. [PubMed: 6101788, related citations] [Full Text: Pubget]

171.	Marino, C. R., Matovcik, L. M., Gorelick, F. S., Cohn, J. A. Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. J. Clin. Invest. 88: 712-716, 1991. [PubMed: 1713921, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

172.	Mateu, E., Calafell, F., Ramos, M. D., Casals, T., Bertranpetit, J. Can a place of origin of the main cystic fibrosis mutations be identified? Am. J. Hum. Genet. 70: 257-264, 2002. [PubMed: 11713719, related citations] [Full Text: Elsevier Science, Pubget]

173.	Matsui, H., Grubb, B. R., Tarran, R., Randell, S. H., Gatzy, J. T., Davis, C. W., Boucher, R. C. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 95: 1005-1015, 1998. [PubMed: 9875854, related citations] [Full Text: Elsevier Science, Pubget]

174.	Mayo, B. J., Klebe, R. J., Barnett, D. R., Lankford, B. J., Bowman, B. H. Somatic cell genetic studies of the cystic fibrosis mucociliary inhibitor. Clin. Genet. 18: 379-386, 1980. [PubMed: 7460374, related citations] [Full Text: Pubget]

175.	McIntosh, I., Lorenzo, M.-L., Brock, D. J. H. Frequency of delta-F508 mutation on cystic fibrosis chromosomes in UK. (Letter) Lancet 334: 1404 only, 1989. Note: Originally Volume 2. [PubMed: 2574356, related citations] [Full Text: Pubget]

176.	McMillan, S. A., Hill, A. J. M., Graham, C. A., Nevin, N. C., Fay, A. C. T cell receptor beta chain polymorphisms are associated with cystic fibrosis. J. Med. Genet. 26: 431-433, 1989. [PubMed: 2568490, related citations] [Full Text: HighWire Press, Pubget]

177.	Mekus, F., Ballmann, M., Bronsveld, I., Dork, T., Bijman, J., Tummler, B., Veeze, H. J. Cystic-fibrosis-like disease unrelated to the cystic fibrosis transmembrane conductance regulator. Hum. Genet. 102: 582-586, 1998. [PubMed: 9654209, related citations] [Full Text: Springer, Pubget]

178.	Mekus, F., Laabs, U., Veeze, H., Tummler, B. Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Hum. Genet. 112: 1-11, 2003. [PubMed: 12483292, related citations] [Full Text: Springer, Pubget]

179.	Meyer, P., Braun, A., Roscher, A. A. Analysis of the two common alpha-1-antitrypsin deficiency alleles PiMS and PiMZ as modifiers of Pseudomonas aeruginosa susceptibility in cystic fibrosis. Clin. Genet. 62: 325-327, 2002. [PubMed: 12372062, related citations] [Full Text: Blackwell Publishing, Pubget]

180.	Mornet, E., Simon-Bouy, B., Serre, J. L., Estivill, X., Farrall, M., Boue, J., Williamson, R., Boue, J., Boue, A. Genetic differences between cystic fibrosis with and without meconium ileus. Lancet 331: 376-378, 1988. Note: Originally Volume 1. [PubMed: 2893188, related citations] [Full Text: Elsevier Science, Pubget]

181.	Mornet, E., Simon-Bouy, B., Serre, J. L., Muller, F., Taillandier, A., Martinez, M., Boue, J., Boue, A. Genetic heterogeneity between two clinical forms of cystic fibrosis evidenced by familial analysis and linked DNA probes. Clin. Genet. 35: 81-87, 1989. [PubMed: 2566403, related citations] [Full Text: Pubget]

182.	Morreau, J., Sinaasappel, M., Oostra, B. A., Halley, D. J. J. Cystic fibrosis: screening for a DNA deletion by field inversion gel electrophoresis. Hum. Genet. 79: 64-67, 1988. [PubMed: 2896622, related citations] [Full Text: Pubget]

183.	Muller, F., Dommergues, M., Simon-Bouy, B., Ferec, C., Oury, J.-F., Aubry, M.-C., Bessis, R., Vuillard, E., Denamur, E., Bienvenu, T., Serre, J.-L. Cystic fibrosis screening: a fetus with hyperechogenic bowel may be the index case. J. Med. Genet. 35: 657-660, 1998. [PubMed: 9719372, related citations] [Full Text: HighWire Press, Pubget]

184.	Mutesa, L., Azad, A. K., Verhaeghe, C., Segers, K., Vanbellinghen, J.-F., Ngendahayo, L., Rusingiza, E. K., Mutwa, P. R., Rulisa, S., Koulischer, L., Cassiman, J.-J., Cuppens, H., Bours, V. Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms: Identification of novel cystic fibrosis transmembrane conductance and epithelial sodium channel gene variants. Chest 135: 1233-1242, 2009. [PubMed: 19017867, related citations] [Full Text: HighWire Press, Pubget]

185.	Nam, M. H., Hijikata, M., Tuan, L. A., Lien, L. T., Shojima, J., Horie, T., Nakata, K., Matsushita, I., Ohashi, J., Tokunaga, K., Keicho, N. Variations of the CFTR gene in the Hanoi-Vietnamese. Am. J. Med. Genet. 136A: 249-253, 2005. [PubMed: 15948196, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

186.	Naylor, S. L., Barnett, D. R., Buchanan, J. M., Latimer, J., Wieder, K., Marshall, S., Gardner, J., Denning, C. R., Gluckson, M., Pinero, R., Rendon, H., Miranda, L. I., Kammerer, C., Zansky, S. M., King, R. H., Bowman, B. H., MacCluer, J. W. Linkage of cystic fibrosis locus and polymorphic DNA markers in 14 families. Am. J. Hum. Genet. 39: 707-712, 1986. [PubMed: 3026173, related citations] [Full Text: Pubget]

187.	Nazer, H., Riff, E., Sakati, N., Mathew, R., Majeed-Saidan, M. A., Harfi, H. Cystic fibrosis in Saudi Arabia. Europ. J. Pediat. 148: 330-332, 1989. [PubMed: 2785036, related citations] [Full Text: Pubget]

188.	Neglia, J. P., FitzSimmons, S. C., Maisonneuve, P., Schoni, M. H., Schoni-Affolter, F., Corey, M., Lowenfels, A. B., Boyle, P., Dozor, A. J., Durie, P. The risk of cancer among patients with cystic fibrosis. New Eng. J. Med. 332: 494-499, 1995. [PubMed: 7830730, related citations] [Full Text: Atypon, Pubget]

189.	Nunes, V., Gasparini, P., Novelli, G., Gaona, A., Bonizzato, A., Sangiuolo, F., Balassopoulou, A., Gimenez, F. J., Dognini, M., Ravnik-Glavac, M., Cikuli, M., Mokini, V., Komel, R., Dallapiccola, B., Pignatti, P. F., Loukopoulos, D., Casals, T., Estivill, X. Analysis of 14 cystic fibrosis mutations in five south European populations. Hum. Genet. 87: 737-738, 1991. [PubMed: 1937479, related citations] [Full Text: Pubget]

190.	O'Sullivan, B. P., Freedman, S. D. Cystic fibrosis. Lancet 373: 1891-1904, 2009. [PubMed: 19403164, related citations] [Full Text: Elsevier Science, Pubget]

191.	Ober, C., Bombard, A., Dhaliwal, R., Elias, S., Fagan, J., Laffler, T. G., Martin, A. O., Rosinsky, B. Studies of cystic fibrosis in Hutterite families by using linked DNA probes. Am. J. Hum. Genet. 41: 1145-1151, 1987. [PubMed: 3479902, related citations] [Full Text: Pubget]

192.	Oppenheimer, E. H. Absence of pancreatic lesions in cystic fibrosis. Birth Defects Orig. Art. Ser. VIII(2): 108-113, 1972.

193.	Oppenheimer, E. H., Case, A. L., Esterly, J. R., Rothberg, R. M. Cervical mucus in cystic fibrosis: a possible cause of infertility. Am. J. Obstet. Gynec. 108: 673-674, 1970. [PubMed: 5505999, related citations] [Full Text: Pubget]

194.	Oppenheimer, E. H., Esterly, J. R. Observations on cystic fibrosis of the pancreas. VI. The uterine cervix. J. Pediat. 77: 991-995, 1970. [PubMed: 5486639, related citations] [Full Text: Pubget]

195.	Oppenheimer, E. H., Esterly, J. R. Observations on cystic fibrosis of the pancreas. V. Developmental changes in the male genital system. J. Pediat. 75: 806-811, 1969. [PubMed: 5357932, related citations] [Full Text: Pubget]

196.	Padoa, C., Goldman, A., Jenkins, T., Ramsay, M. Cystic fibrosis carrier frequencies in populations of African origin. J. Med. Genet. 36: 41-44, 1999. [PubMed: 9950364, related citations] [Full Text: HighWire Press, Pubget]

197.	Park, M., Testa, J. R., Blair, D. G., Dean, M., Parsa, N. Z., Vande Woude, G. F. The CF locus is distal to and upstream from the met protooncogene transcription unit which is located at 7q31-32. Cytogenet. Cell Genet. 46: 674-675, 1987.

198.	Pier, G. B., Grout, M., Zaidi, T., Meluleni, G., Mueschenborn, S. S., Banting, G., Ratcliff, R., Evans, M. J., Colledge, W. H. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 393: 79-82, 1998. [PubMed: 9590693, related citations] [Full Text: Nature Publishing Group, Pubget]

199.	Pier, G. B., Grout, M., Zaldi, T. S., Olsen, J. C., Johnson, L. G., Yankaskas, J. R., Goldberg, J. B. Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 271: 63-67, 1996.

200.	Quint, A., Lerer, I., Sagi, M., Abeliovich, D. Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am. J. Med. Genet. 136A: 246-248, 2005. [PubMed: 15948195, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

201.	Quinton, P. M. Chloride impermeability in cystic fibrosis. Nature 301: 421-422, 1983. [PubMed: 6823316, related citations] [Full Text: Pubget]

202.	Rao, G. J. S., Nadler, H. L. Deficiency of arginine esterase in cystic fibrosis of pancreas--demonstration of proteolytic nature of activity. Pediat. Res. 9: 739-741, 1975. [PubMed: 1202423, related citations] [Full Text: Pubget]

203.	Rao, G. J. S., Nadler, H. L. Arginine esterase in cystic fibrosis of the pancreas. Pediat. Res. 8: 684-686, 1974. [PubMed: 4838499, related citations] [Full Text: Pubget]

204.	Rao, G. J. S., Posner, L. A., Nadler, H. L. Deficiency of kallikrein activity in plasma of patients with cystic fibrosis. Science 177: 610-611, 1972. [PubMed: 4538064, related citations] [Full Text: HighWire Press, Pubget]

205.	Reddy, M. M., Light, M. J., Quinton, P. M. Activation of the epithelial Na(+) channel (ENaC) requires CFTR CI(-) channel function. Nature 402: 301-304, 1999. [PubMed: 10580502, related citations] [Full Text: Nature Publishing Group, Pubget]

206.	Restrepo, C. M., Pineda, L., Rojas-Martinez, A., Gutierrez, C. A., Morales, A., Gomez, Y., Villalobos, M. C., Borjas, L., Delgado, W., Myers, A., Barrera-Saldana, H. A. CFTR mutations in three Latin American countries. Am. J. Med. Genet. 91: 277-279, 2000. [PubMed: 10766983, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

207.	Rich, D. P., Anderson, M. P., Gregory, R. J., Cheng, S. H., Paul, S., Jefferson, D. M., McCann, J. D., Klinger, K. W., Smith, A. E., Welsh, M. J. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 347: 358-363, 1990. [PubMed: 1699126, related citations] [Full Text: Nature Publishing Group, Pubget]

208.	Roberts, G. B. S. Familial incidence of fibrocystic disease of the pancreas. Ann. Hum. Genet. 24: 127-135, 1960. [PubMed: 14437811, related citations] [Full Text: Pubget]

209.	Rodman, D. M., Zamudio, S. The cystic fibrosis heterozygote--advantage in surviving cholera? Med. Hypotheses 36: 253-258, 1991. [PubMed: 1724059, related citations] [Full Text: Elsevier Science, Pubget]

210.	Rogers, C. S., Stoltz, D. A., Meyerholz, D. K., Ostedgaard, L. S., Rokhlina, T., Taft, P. J., Rogan, M. P., Pezzulo, A. A., Karp, P. H., Itani, O. A., Kabel, A. C., Wohlford-Lenane, C. L., and 16 others. Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321: 1837-1841, 2008. [PubMed: 18818360, related citations] [Full Text: HighWire Press, Pubget]

211.	Romeo, G., Bianco, M., Devoto, M., Menozzi, P., Mastella, G., Giunta, A. M., Micalizzi, C., Antonelli, M., Battistini, A., Santamaria, F., Castello, D., Marianelli, A., Marchi, A. G., Manca, A., Miano, A. Incidence in Italy, genetic heterogeneity, and segregation analysis of cystic fibrosis. Am. J. Hum. Genet. 37: 338-349, 1985. [PubMed: 3985009, related citations] [Full Text: Pubget]

212.	Romeo, G., Devoto, M., Bianco, M. Homogeneity vs. heterogeneity of cystic fibrosis in Italy. (Letter) Am. J. Hum. Genet. 39: 283-284, 1986. [PubMed: 3752092, related citations] [Full Text: Pubget]

213.	Romeo, G., Devoto, M., Galietta, L. J. V. Why is the cystic fibrosis gene so frequent? Hum. Genet. 84: 1-5, 1989. [PubMed: 2691388, related citations] [Full Text: Pubget]

214.	Rosenfeld, M. A., Yoshimura, K., Trapnell, B. C., Yoneyama, K., Rosenthal, E. R., Dalemans, W., Fukayama, M., Bargon, J., Stier, L. E., Stratford-Perricaudet, L., Perricaudet, M., Guggino, W. B., Pavirani, A., Lecocq, J.-P., Crystal, R. G. In vivo transfer of the human cystic fibrosis transmembrane conductance regulator gene to the airway epithelium. Cell 68: 143-155, 1992. [PubMed: 1370653, related citations] [Full Text: Elsevier Science, Pubget]

215.	Rozmahel, R., Wilschanski, M., Matin, A., Plyte, S., Oliver, M., Auerbach, W., Moore, A., Forstner, J., Durie, P., Nadeau, J., Bear, C., Tsui, L.-C. Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nature Genet. 12: 280-287, 1996. [PubMed: 8589719, related citations] [Full Text: Nature Publishing Group, Pubget]

216.	Sanguinetti-Briceno, N. R., Brock, D. J. H. NADH dehydrogenase in cystic fibrosis. Clin. Genet. 22: 308-311, 1982. [PubMed: 7160101, related citations] [Full Text: Pubget]

217.	Savov, A., Angelicheva, D., Balassopoulou, A., Jordanova, A., Noussia-Arvanitakis, S., Kalaydjieva, L. Double mutant alleles: are they rare? Hum. Molec. Genet. 4: 1169-1171, 1995. [PubMed: 8528204, related citations] [Full Text: HighWire Press, Pubget]

218.	Scambler, P., Robbins, T., Gilliam, C., Boylston, A., Tippett, P., Williamson, R., Davies, K. E. Linkage studies between polymorphic markers on chromosome 4 and cystic fibrosis. Hum. Genet. 69: 250-254, 1985. [PubMed: 2984105, related citations] [Full Text: Pubget]

219.	Scambler, P. J., Wainwright, B. J., Farrall, M., Bell, J., Stanier, P., Lench, N. J., Bell, G., Kruyer, H., Ramirez, F., Williamson, R. Linkage of COL1A2 collagen gene to cystic fibrosis, and its clinical implications. (Letter) Lancet 326: 1241-1242, 1985. Note: Originally Volume 2. [PubMed: 2866313, related citations] [Full Text: Elsevier Science, Pubget]

220.	Scambler, P. J., Wainwright, B. J., Watson, E., Bates, G., Bell, G., Williamson, R., Farrall, M. Isolation of a further anonymous informative DNA sequence from chromosome seven closely linked to cystic fibrosis. Nucleic Acids Res. 14: 1951-1956, 1986. [PubMed: 3960715, related citations] [Full Text: HighWire Press, Pubget]

221.	Schoumacher, R. A., Ram, J., Iannuzzi, M. C., Bradbury, N. A., Wallace, R. W., Tom Hon, C., Kelly, D. R., Schmid, S. M., Gelder, F. B., Rado, T. A., Frizzell, R. A. A cystic fibrosis pancreatic adenocarcinoma cell line. Proc. Nat. Acad. Sci. 87: 4012-4016, 1990. [PubMed: 1692630, related citations] [Full Text: HighWire Press, Pubget]

222.	Scotet, V., Audrezet, M.-P., Roussey, M., Rault, G., Blayau, M., De Braekeleer, M., Ferec, C. Impact of public health strategies on the birth prevalence of cystic fibrosis in Brittany, France. Hum. Genet. 113: 280-285, 2003. [PubMed: 12768409, related citations] [Full Text: Springer, Pubget]

223.	Scotet, V., De Braekeleer, M., Audrezet, M.-P., Quere, I., Mercier, B., Dugueperoux, I., Andrieux, J., Blayau, M., Ferec, C. Prenatal detection of cystic fibrosis by ultrasonography: a retrospective study of more than 346 000 pregnancies. J. Med. Genet. 39: 443-448, 2002. [PubMed: 12070257, related citations] [Full Text: HighWire Press, Pubget]

224.	Scotet, V., Gillet, D., Dugueperoux, I., Audrezet, M.-P., Bellis, G., Garnier, B., Roussey, M., Rault, G., Parent, P., De Braekeleer, M., Ferec, C. Spatial and temporal distribution of cystic fibrosis and of its mutations in Brittany, France: a retrospective study from 1960. Hum. Genet. 111: 247-254, 2002. [PubMed: 12215837, related citations] [Full Text: Springer, Pubget]

225.	Scully, R. E., Goldabini, J. J., McNeely, B. V. Case reports of the Massachusetts General Hospital (CPCs). New Eng. J. Med. 296: 1519-1526, 1977. [PubMed: 865535, related citations] [Full Text: Atypon, Pubget]

226.	Searle, A. G., Peters, J., Lyon, M. F., Evans, E. P., Edwards, J. H., Bauckle, B. J. Chromosome maps of man and mouse, III. Genomics 1: 3-18, 1987. [PubMed: 3311967, related citations] [Full Text: Elsevier Science, Pubget]

227.	Shapiro, B. L., Lam, L. F.-H. Calcium and age in fibroblasts from control subjects and patients with cystic fibrosis. Science 216: 417-419, 1982. [PubMed: 7071590, related citations] [Full Text: HighWire Press, Pubget]

228.	Shapiro, B. L., Lam, L. F.-H., Feigal, R. J. Mitochondrial NADH dehydrogenase in cystic fibrosis: enzyme kinetics in cultured fibroblasts. Am. J. Hum. Genet. 34: 846-852, 1982. [PubMed: 7180843, related citations] [Full Text: Pubget]

229.	Sharer, N., Schwarz, M., Malone, G., Howarth, A., Painter, J., Super, M., Braganza, J. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. New Eng. J. Med. 339: 645-652, 1998. [PubMed: 9725921, related citations] [Full Text: Atypon, Pubget]

230.	Shepherd, R. W., Holt, T. L., Vasques-Velasquez, L., Coward, W. A., Prentice, A., Lucas, A. Increased energy expenditure in young children with cystic fibrosis. Lancet 331: 1300-1303, 1988. Note: Originally Volume 1. [PubMed: 2897557, related citations] [Full Text: Elsevier Science, Pubget]

231.	Sheppard, D. N., Rich, D. P., Ostedgaard, L. S., Gregory, R. J., Smith, A. E., Welsh, M. J. Mutations in CFTR associated with mild-disease form CI- channels with altered pore properties. Nature 362: 160-164, 1993. [PubMed: 7680769, related citations] [Full Text: Nature Publishing Group, Pubget]

232.	Sheridan, M. B., Fong, P., Groman, J. D., Conrad, C., Flume, P., Diaz, R., Harris, C., Knowles, M., Cutting, G. R. Mutations in the beta-subunit of the epithelial Na(+) channel in patients with a cystic fibrosis-like syndrome. Hum. Molec. Genet. 14: 3493-3498, 2005. [PubMed: 16207733, related citations] [Full Text: HighWire Press, Pubget]

233.	Shier, W. T. Increased resistance to influenza as a possible source of heterozygote advantage in cystic fibrosis. Med. Hypotheses 5: 661-667, 1979. [PubMed: 226848, related citations] [Full Text: Elsevier Science, Pubget]

234.	Shwachman, H., Kowalski, M., Khaw, K.-T. Cystic fibrosis: a new outlook: 70 patients above 25 years of age. Medicine 56: 129-149, 1977. [PubMed: 846387, related citations] [Full Text: Pubget]

235.	Sing, C. F., Risser, D. R., Howatt, W. F., Erickson, R. P. Phenotypic heterogeneity in cystic fibrosis. Am. J. Med. Genet. 13: 179-195, 1982. [PubMed: 7137230, related citations] [Full Text: Pubget]

236.	Siraganian, P. A., Miller, R. W., Swender, P. T. Cystic fibrosis and ileal carcinoma. (Letter) Lancet 330: 1158 only, 1987. Note: Originally Volume 2. [PubMed: 2890063, related citations] [Full Text: Pubget]

237.	Smith, D. W., Docter, J. M., Ferrier, P. E., Frias, J. L., Spock, A. Possible localisation of the gene for cystic fibrosis of the pancreas to the short arm of chromosome 5. Lancet 292: 309-311, 1968. Note: Originally Volume 2. [PubMed: 4173733, related citations] [Full Text: Pubget]

238.	Smyth, R. L. Fibrosing colonopathy in cystic fibrosis. Arch. Child. Dis. 74: 464-466, 1996.

239.	Smyth, R. L., van Velzen, D., Smyth, A. R., Lloyd, D. A., Heaf, D. P. Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet 343: 85-86, 1994. [PubMed: 7903780, related citations] [Full Text: Elsevier Science, Pubget]

240.	Snouwaert, J. N., Brigman, K. K., Latour, A. M., Malouf, N. N., Boucher, R. C., Smithies, O., Koller, B. H. An animal model for cystic fibrosis made by gene targeting. Science 257: 1083-1088, 1992. [PubMed: 1380723, related citations] [Full Text: HighWire Press, Pubget]

241.	Spence, J. E., Perciaccante, R. G., Greig, G. M., Willard, H. F., Ledbetter, D. H., Hejtmancik, J. F., Pollack, M. S., O'Brien, W. E., Beaudet, A. L. Uniparental disomy as a mechanism for human genetic disease. Am. J. Hum. Genet. 42: 217-226, 1988. [PubMed: 2893543, related citations] [Full Text: Pubget]

242.	Spence, J. E., Rosenbloom, C. L., O'Brien, W. E., Seilheimer, D. K., Cole, S., Ferrell, R. E., Stern, R. C., Beaudet, A. L. Linkage of DNA markers to cystic fibrosis in 26 families. Am. J. Hum. Genet. 39: 729-734, 1986. [PubMed: 2879439, related citations] [Full Text: Pubget]

243.	Spock, A., Heick, H. M. C., Cress, H., Logan, W. S. Abnormal serum factor in patients with cystic fibrosis of the pancreas. Pediat. Res. 1: 173-177, 1967. [PubMed: 6080862, related citations] [Full Text: Pubget]

244.	Stanke, F., Becker, T., Cuppens, H., Kumar, V., Cassiman, J.-J., Jansen, S., Radojkovic, D., Siebert, B., Yarden, J., Ussery, D. W., Wienker, T. F., Tummler, B. The TNF-alpha receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis. Hum. Genet. 119: 331-343, 2006. [PubMed: 16463024, related citations] [Full Text: Springer, Pubget]

245.	Steinberg, A. G., Brown, D. C. On the incidence of cystic fibrosis of the pancreas. Am. J. Hum. Genet. 12: 416-424, 1960. [PubMed: 17948456, related citations] [Full Text: Pubget]

246.	Stern, R. C. The diagnosis of cystic fibrosis. New Eng. J. Med. 336: 487-491, 1997. [PubMed: 9017943, related citations] [Full Text: Atypon, Pubget]

247.	Stern, R. C., Boat, T. F., Abramowsky, C. R., Matthews, L. W., Wood, R. E., Daershuk, C. F. Intermediate-range sweat chloride concentration and Pseudomonas bronchitis: a cystic fibrosis variant with preservation of exocrine pancreatic function. JAMA 239: 2676-2680, 1978. [PubMed: 650841, related citations] [Full Text: Pubget]

248.	Stern, R. C., Boat, T. F., Doershuk, C. F. Obstructive azoospermia as a diagnostic criterion for the cystic fibrosis syndrome. Lancet 319: 1401-1404, 1982. Note: Originally Volume 1. [PubMed: 6123689, related citations] [Full Text: Pubget]

249.	Strain, L., Curtis, A., Mennie, M., Holloway, S., Brock, D. J. H. Use of linkage disequilibrium data in prenatal diagnosis of cystic fibrosis. Hum. Genet. 80: 75-77, 1988. [PubMed: 3417307, related citations] [Full Text: Pubget]

250.	Super, M. Genetic counselling and antenatal diagnosis of cystic fibrosis. J. Roy. Soc. Med. 80: 13-15, 1987. [PubMed: 3477643, related citations] [Full Text: Pubget]

251.	Tarran, R., Grubb, B. R., Parsons, D., Picher, M., Hirsh, A. J., Davis, C. W., Boucher, R. C. The CF salt controversy: in vivo observations and therapeutic approaches. Molec. Cell 8: 149-158, 2001. [PubMed: 11511368, related citations] [Full Text: Elsevier Science, Pubget]

252.	Tebbutt, S. J., Wardle, C. J. C., Hill, D. F., Harris, A. Molecular analysis of the ovine cystic fibrosis transmembrane conductance regulator gene. Proc. Nat. Acad. Sci. 92: 2293-2297, 1995. [PubMed: 7534416, related citations] [Full Text: HighWire Press, Pubget]

253.	Ten Kate, L. P., Scheffer, H., Cornel, M. C., vanLookeren Campagne, J. G. Consanguinity sans reproche. Hum. Genet. 86: 295-296, 1991. [PubMed: 1997385, related citations] [Full Text: Pubget]

254.	The Cystic Fibrosis Genotype-Phenotype Consortium. Correlation between genotype and phenotype in patients with cystic fibrosis. New Eng. J. Med. 329: 1308-1313, 1993. [PubMed: 8166795, related citations] [Full Text: Atypon, Pubget]

255.	Tsui, L.-C., Buchwald, M., Barker, D., Braman, J. C., Knowlton, R., Schumm, J. W., Eiberg, H., Mohr, J., Kennedy, D., Plavsic, N., Zsiga, M., Markiewicz, D., Akots, G., Brown, V., Helms, C., Gravius, T., Parker, C., Rediker, K., Donis-Keller, H. Cystic fibrosis locus defined by a genetically linked polymorphic DNA marker. Science 230: 1054-1057, 1985. [PubMed: 2997931, related citations] [Full Text: HighWire Press, Pubget]

256.	Tsui, L.-C., Buetow, K., Buchwald, M. Genetic analysis of cystic fibrosis using linked DNA markers. Am. J. Hum. Genet. 39: 720-728, 1986. [PubMed: 3467587, related citations] [Full Text: Pubget]

257.	van de Vosse, E., Ali, S., de Visser, A. W., Surjadi, C., Widjaja, S., Vollaard, A. M., van Dissel, J. T. Susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR). Hum. Genet. 118: 138-140, 2005. [PubMed: 16078047, related citations] [Full Text: Springer, Pubget]

258.	Viel, M., Leroy, C., Hubert, D., Fajac, I., Bienvenu, T. ENaC-beta and -gamma genes as modifier genes in cystic fibrosis. J. Cyst. Fibros. 7: 23-29, 2008. [PubMed: 17560176, related citations] [Full Text: Elsevier Science, Pubget]

259.	Vitale, E., Devoto, M., Mastella, G., Romeo, G. Homogeneity of cystic fibrosis in Italy. Am. J. Hum. Genet. 39: 832-836, 1986. [PubMed: 3467589, related citations] [Full Text: Pubget]

260.	Voss, R., Ben-Simon, E., Avital, A., Godfrey, S., Zlotogora, J., Dagan, J., Tikochinski, T., Hillel, J. Isodisomy of chromosome 7 in a patient with cystic fibrosis: could uniparental disomy be common in humans? Am. J. Hum. Genet. 45: 373-380, 1989. [PubMed: 2570528, related citations] [Full Text: Pubget]

261.	Voss, R., Ben-Simon, E., Zlotogora, Y., Dagan, J., Godfry, S., Haberfeld, A., Hillel, Y. Uniparental disomy for chromosome 7--cause for homozygosity at the cystic fibrosis locus. (Abstract) Am. J. Hum. Genet. 43: A73 only, 1988.

262.	Wainwright, B., Scambler, P., Farrall, M., Schwartz, M., Williamson, R. Linkage between the cystic fibrosis locus and markers on chromosome 7q. Cytogenet. Cell Genet. 41: 191-192, 1986. [PubMed: 3956271, related citations] [Full Text: Pubget]

263.	Wainwright, B. J., Scambler, P. J., Schmidtke, J., Watson, E. A., Law, H.-Y., Farrall, M., Cooke, H. J., Eiberg, H., Williamson, R. Localization of cystic fibrosis locus to human chromosome 7cen-q22. Nature 318: 384-385, 1985. [PubMed: 2999612, related citations] [Full Text: Pubget]

264.	Wang, J., Bowman, M. C., Hsu, E., Wertz, K., Wong, L.-J. C. A novel mutation in the CFTR gene correlates with severe clinical phenotype in seven Hispanic patients. J. Med. Genet. 37: 215-218, 2000. [PubMed: 10777364, related citations] [Full Text: HighWire Press, Pubget]

265.	Warner, J. O., Norman, A. P., Soothill, J. F. Cystic fibrosis heterozygosity in the pathogenesis of allergy. Lancet 307: 990-991, 1976. Note: Originally Volume 1. [PubMed: 57442, related citations] [Full Text: Elsevier Science, Pubget]

266.	Watkins, P. C., Schwartz, R., Hoffman, N., Stanislovitis, P., Doherty, R., Klinger, K. A linkage study of cystic fibrosis is extended multigenerational pedigrees. Am. J. Hum. Genet. 39: 735-743, 1986. [PubMed: 2879440, related citations] [Full Text: Pubget]

267.	Welsh, M. J., Fick, R. B. Cystic fibrosis. J. Clin. Invest. 80: 1523-1526, 1987. [PubMed: 3316277, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

268.	White, R., Leppert, M., O'Connell, P., Nakamura, Y., Woodward, S., Hoff, M., Herbst, J., Dean, M., Vande Woude, G., Lathrop, G. M., Lalouel, J.-M. Further linkage data on cystic fibrosis: the Utah study. Am. J. Hum. Genet. 39: 694-698, 1986. [PubMed: 2879438, related citations] [Full Text: Pubget]

269.	White, R., Woodward, S., Leppert, M., O'Connell, P., Hoff, M., Herbst, J., Lalouel, J.-M., Dean, M., Vande Woude, G. A closely linked genetic marker for cystic fibrosis. Nature 318: 382-384, 1985. [PubMed: 3906407, related citations] [Full Text: Pubget]

270.	Widdicombe, J. H., Welsh, M. J., Finkbeiner, W. E. Cystic fibrosis decreases the apical membrane chloride permeability of monolayers cultured from cells of tracheal epithelium. Proc. Nat. Acad. Sci. 82: 6167-6171, 1985. [PubMed: 3862125, related citations] [Full Text: HighWire Press, Pubget]

271.	Williamson, R. Personal Communication. London, England 11/22/1984.

272.	Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J., Campbell, K. H. S. Viable offspring derived from fetal and adult mammalian cells. Nature 385: 810-813, 1997. [PubMed: 9039911, related citations] [Full Text: Nature Publishing Group, Pubget]

273.	Wilson, G. B., Fudenberg, H. H., Jahn, T. L. Studies on cystic fibrosis using isoelectric focusing. I. An assay for detection of cystic fibrosis homozygotes and heterozygote carriers from serum. Pediat. Res. 9: 635-640, 1975. [PubMed: 239381, related citations] [Full Text: Pubget]

274.	Wilson, J. M. Gene therapy for cystic fibrosis: challenges and future directions. J. Clin. Invest. 96: 2547-2554, 1995. [PubMed: 8675618, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

275.	Wine, J. J. No CFTR: are CF symptoms milder? (Letter) Nature Genet. 1: 10 only, 1992. [PubMed: 1284545, related citations] [Full Text: Nature Publishing Group, Pubget]

276.	Woo, S. Personal Communication. Houston, Tex. 1988.

277.	Wright, S. W., Morton, N. E. Genetic studies on cystic fibrosis in Hawaii. Am. J. Hum. Genet. 20: 157-162, 1968. [PubMed: 5643180, related citations] [Full Text: Pubget]

278.	Yang, Y., Devor, D. C., Engelhardt, J. F., Ernst, S. A., Strong, T. V., Collins, F. S., Cohn, J. A., Frizzell, R. A., Wilson, J. M. Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR. Hum. Molec. Genet. 2: 1253-1261, 1993. [PubMed: 7691345, related citations] [Full Text: HighWire Press, Pubget]

279.	Yang, Y., Raper, S. E., Cohn, J. A., Engelhardt, J. F., Wilson, J. M. An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer. Proc. Nat. Acad. Sci. 90: 4601-4605, 1993. [PubMed: 7685107, related citations] [Full Text: HighWire Press, Pubget]

280.	Yarden, J., Radojkovic, D., De Boeck, K., Macek, M., Jr., Zemkova, D., Vavrova, V., Vlietinck, R., Cassiman, J.-J., Cuppens, H. Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype. J. Med. Genet. 41: 629-633, 2004. [PubMed: 15286159, related citations] [Full Text: HighWire Press, Pubget]

281.	Zhou, L., Dey, C. R., Wert, S. E., DuVall, M. D., Frizzell, R. A., Whitsett, J. A. Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science 266: 1705-1708, 1994. [PubMed: 7527588, related citations] [Full Text: HighWire Press, Pubget]

Contributors:	Ada Hamosh - updated : 9/7/2011
	Ada Hamosh - updated : 5/23/2011 Patricia A. Hartz - updated : 3/17/2011 Ada Hamosh - updated : 5/27/2010 Marla J. F. O'Neill - updated : 10/5/2009 Marla J. F. O'Neill - updated : 10/1/2009 Cassandra L. Kniffin - updated : 5/18/2009 Ada Hamosh - updated : 5/11/2009 Ada Hamosh - updated : 10/22/2008 Ada Hamosh - updated : 7/25/2008 Cassandra L. Kniffin - updated : 6/2/2008 John A. Phillips, III - updated : 9/28/2007 Marla J. F. O'Neill - updated : 6/7/2007 Cassandra L. Kniffin - updated : 5/12/2006 Paul J. Converse - updated : 2/8/2006 Victor A. McKusick - updated : 10/17/2005 Victor A. McKusick - updated : 10/14/2005 Marla J. F. O'Neill - updated : 4/20/2005 Marla J. F. O'Neill - updated : 12/9/2004 Ada Hamosh - updated : 6/2/2004 Ada Hamosh - updated : 4/30/2004 Victor A. McKusick - updated : 2/24/2004 Victor A. McKusick - updated : 8/13/2003 Victor A. McKusick - updated : 3/27/2003 Victor A. McKusick - updated : 2/4/2003 Victor A. McKusick - updated : 12/30/2002 Victor A. McKusick - updated : 11/6/2002 Victor A. McKusick - updated : 10/16/2002 Victor A. McKusick - updated : 8/21/2002 Michael J. Wright - updated : 6/28/2002 Deborah L. Stone - updated : 4/11/2002 Victor A. McKusick - updated : 1/22/2002 Stylianos E. Antonarakis - updated : 8/3/2001 Michael J. Wright - updated : 7/24/2001 Michael J. Wright - updated : 6/5/2001 Michael J. Wright - updated : 1/10/2001 Sonja A. Rasmussen - updated : 9/21/2000 Sonja A. Rasmussen - updated : 9/18/2000 Ada Hamosh - updated : 9/13/2000 Ada Hamosh - updated : 7/20/2000 Ada Hamosh - updated : 2/9/2000 Ada Hamosh - updated : 11/22/1999 Victor A. McKusick - updated : 10/11/1999 Ada Hamosh - updated : 4/7/1999 Victor A. McKusick - updated : 3/16/1999 Michael J. Wright - updated : 2/12/1999 Stylianos E. Antonarakis - updated : 2/4/1999 Michael J. Wright - updated : 11/16/1998 Victor A. McKusick - updated : 9/18/1998 Victor A. McKusick - updated : 9/14/1998 Ada Hamosh - updated : 5/18/1998 Victor A. McKusick - updated : 5/9/1998 Victor A. McKusick - updated : 5/9/1998 Clair A. Francomano - updated : 5/7/1998 Victor A. McKusick - updated : 4/23/1998 John F. Jackson - reorganized : 3/7/1998 Victor A. McKusick - updated : 12/19/1997 Victor A. McKusick - updated : 11/10/1997 Victor A. McKusick - updated : 10/10/1997 Victor A. McKusick - updated : 6/26/1997 Victor A. McKusick - updated : 6/16/1997 Victor A. McKusick - updated : 6/5/1997 Victor A. McKusick - updated : 5/15/1997 Victor A. McKusick - updated : 3/16/1997 Victor A. McKusick - updated : 3/6/1997 Victor A. McKusick - updated : 2/28/1997
Creation Date:	Victor A. McKusick : 6/3/1986
Edit History:	alopez : 09/08/2011
	terry : 9/7/2011 alopez : 5/24/2011 terry : 5/23/2011 terry : 3/18/2011 mgross : 3/17/2011 terry : 10/12/2010 carol : 8/13/2010 alopez : 6/2/2010 terry : 5/27/2010 carol : 4/29/2010 wwang : 10/29/2009 wwang : 10/28/2009 wwang : 10/12/2009 wwang : 10/7/2009 terry : 10/5/2009 wwang : 10/1/2009 wwang : 9/18/2009 terry : 9/3/2009 wwang : 6/12/2009 terry : 6/4/2009 terry : 6/3/2009 ckniffin : 5/18/2009 alopez : 5/13/2009 terry : 5/11/2009 terry : 4/9/2009 alopez : 10/22/2008 alopez : 7/30/2008 terry : 7/25/2008 wwang : 6/17/2008 ckniffin : 6/2/2008 carol : 10/10/2007 alopez : 9/28/2007 wwang : 6/13/2007 terry : 6/7/2007 terry : 11/15/2006 carol : 6/29/2006 wwang : 5/17/2006 ckniffin : 5/12/2006 carol : 2/8/2006 carol : 1/19/2006 alopez : 10/27/2005 alopez : 10/24/2005 terry : 10/17/2005 terry : 10/14/2005 wwang : 10/11/2005 wwang : 5/23/2005 wwang : 4/28/2005 wwang : 4/26/2005 terry : 4/20/2005 tkritzer : 12/9/2004 alopez : 6/2/2004 terry : 6/2/2004 alopez : 5/3/2004 terry : 4/30/2004 tkritzer : 2/27/2004 terry : 2/24/2004 carol : 2/19/2004 tkritzer : 11/7/2003 ckniffin : 11/3/2003 tkritzer : 8/19/2003 terry : 8/13/2003 terry : 8/13/2003 cwells : 4/2/2003 terry : 3/27/2003 carol : 2/28/2003 tkritzer : 2/19/2003 terry : 2/4/2003 carol : 1/7/2003 tkritzer : 1/2/2003 terry : 12/30/2002 terry : 11/22/2002 carol : 11/13/2002 tkritzer : 11/12/2002 terry : 11/6/2002 carol : 10/17/2002 tkritzer : 10/16/2002 tkritzer : 10/16/2002 mgross : 10/14/2002 terry : 8/21/2002 alopez : 6/28/2002 terry : 6/28/2002 carol : 4/11/2002 carol : 2/4/2002 terry : 1/22/2002 carol : 9/10/2001 mgross : 8/3/2001 mgross : 8/3/2001 alopez : 8/2/2001 terry : 7/24/2001 alopez : 6/5/2001 alopez : 1/10/2001 mcapotos : 1/9/2001 terry : 12/13/2000 alopez : 10/3/2000 carol : 9/22/2000 mcapotos : 9/22/2000 mcapotos : 9/21/2000 mcapotos : 9/18/2000 mcapotos : 9/18/2000 terry : 9/13/2000 mcapotos : 8/1/2000 mcapotos : 7/28/2000 terry : 7/20/2000 alopez : 2/9/2000 alopez : 11/22/1999 terry : 11/22/1999 mgross : 10/11/1999 mgross : 7/14/1999 alopez : 4/7/1999 terry : 3/16/1999 mgross : 3/3/1999 mgross : 3/1/1999 terry : 2/12/1999 carol : 2/4/1999 dkim : 12/10/1998 alopez : 12/8/1998 terry : 11/16/1998 carol : 9/28/1998 terry : 9/18/1998 carol : 9/17/1998 terry : 9/14/1998 dkim : 7/24/1998 terry : 6/4/1998 alopez : 5/18/1998 alopez : 5/9/1998 alopez : 5/9/1998 alopez : 5/9/1998 dholmes : 5/7/1998 dholmes : 5/7/1998 alopez : 4/23/1998 carol : 4/17/1998 carol : 3/30/1998 carol : 3/28/1998 carol : 3/7/1998 terry : 1/8/1998 mark : 1/2/1998 dholmes : 12/31/1997 terry : 12/19/1997 terry : 11/14/1997 terry : 11/10/1997 jenny : 10/17/1997 terry : 10/10/1997 joanna : 8/12/1997 terry : 7/25/1997 terry : 7/10/1997 terry : 7/9/1997 terry : 6/26/1997 mark : 6/20/1997 mark : 6/18/1997 terry : 6/16/1997 terry : 6/5/1997 mark : 5/26/1997 mark : 5/16/1997 jenny : 5/15/1997 terry : 5/12/1997 mark : 3/16/1997 terry : 3/10/1997 mark : 3/6/1997 terry : 3/5/1997 mark : 2/28/1997 terry : 2/26/1997 jamie : 2/18/1997 jenny : 1/10/1997 terry : 1/8/1997 terry : 12/30/1996 jamie : 11/15/1996 terry : 11/11/1996 terry : 10/24/1996 jamie : 10/23/1996 jamie : 10/16/1996 jamie : 10/16/1996 jamie : 10/16/1996 mark : 8/30/1996 carol : 8/23/1996 marlene : 8/2/1996 terry : 7/26/1996 mark : 7/17/1996 mark : 6/25/1996 mark : 6/24/1996 terry : 6/18/1996 terry : 5/10/1996 mark : 4/28/1996 mark : 4/25/1996 terry : 4/22/1996 mark : 2/29/1996 terry : 2/27/1996 mark : 2/23/1996 mark : 2/6/1996 terry : 1/31/1996 mark : 1/27/1996 mark : 1/21/1996 terry : 1/19/1996 mark : 1/14/1996 mark : 1/4/1996 terry : 1/4/1996 mark : 11/14/1995 terry : 11/2/1995 davew : 8/16/1994 jason : 6/28/1994 warfield : 4/15/1994 pfoster : 3/24/1994

Table of Contents - #219700

External Links:

Clinical Resources

Animal Models

Cell Lines

Cellular Pathways

		Sort by: Relevance Date updated
Advanced Search: OMIM, Clinical Synopses, OMIM Gene Map Search History: View, Clear