OMIM Entry - +107730 - APOLIPOPROTEIN B; APOB

+107730 ICD+

SNOMEDCT: 442411007,
SNOMEDCT: 102724007,
ICD10CM: E78.6

SNOMEDCT: 442411007, SNOMEDCT: 102724007, ICD10CM: E78.6

APOLIPOPROTEIN B; APOB

Other entities represented in this entry:

LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 4, INCLUDED; LDLCQ4, INCLUDED

HYPOBETALIPOPROTEINEMIA, FAMILIAL, INCLUDED; FHBL, INCLUDED
HYPOBETALIPOPROTEINEMIA, FAMILIAL, 1, INCLUDED; FHBL1, INCLUDED
ACANTHOCYTOSIS WITH HYPOBETALIPOPROTEINEMIA, INCLUDED
HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC, INCLUDED
APOB100, INCLUDED
APOB48, INCLUDED
APOLIPOPROTEIN B ALLOTYPES, INCLUDED
Ag LIPOPROTEIN TYPES, INCLUDED

HGNC Approved Gene Symbol: APOB

Cytogenetic location: 2p24.1 Genomic coordinates (GRCh37): 2:21,224,300 - 21,266,944 (from NCBI)

Gene Phenotype Relationships

Location	Phenotype	Phenotype MIM number
2p24.1	Hypercholesterolemia, due to ligand-defective apo B	144010
	Hypobetalipoproteinemia
	Hypobetalipoproteinemia, normotriglyceridemic

Clinical Synopsis

TEXT

Apolipoprotein B is the main apolipoprotein of chylomicrons and low density lipoproteins (LDL). It occurs in the plasma in 2 main forms, apoB48 and apoB100. The first is synthesized exclusively by the gut, the second by the liver. Lusis et al. (1985) identified cDNA clones for human apoB; examination of a somatic cell panel indicated that the APOB gene resides on chromosome 2, unlinked to the 3 other apolipoprotein clusters. Law et al. (1985) cloned the gene and assigned it to chromosome 2 by filter hybridization with DNA from human/mouse somatic cell hybrids. By somatic cell hybrid studies and by in situ hybridization, Knott et al. (1985) assigned the gene to the tip of 2p in band p24. Deeb et al. (1986) used a hybridization probe to detect homologous sequences in both flow-sorted and in situ metaphase chromosomes. The gene was assigned to 2p24-p23. They found, furthermore, that RNA isolated from monkey small intestine contained sequences homologous to the cDNA of apolipoprotein B100. These results were interpreted as indicating that intestinal (B48) and hepatic (B100) forms of apoB are coded by a single gene. Glickman et al. (1986) found a single mRNA transcript for apoB regardless of the form of apoB (apoB100 or apoB48) synthesized in the liver or intestine. From study of chromosomal aberrations in somatic cell hybrids, Huang et al. (1986) concluded that the APOB locus is located in either the 2p21-p23 or the 2pter-p24 segment. Mehrabian et al. (1986) localized APOB to 2p24-p23 by somatic cell hybridization and in situ hybridization. Filter hybridization studies with genomic DNA and with hepatic and intestinal mRNA suggested that hepatic and intestinal apoB are derived from the same gene. Hospattankar et al. (1986) presented some immunologic data suggesting that the 2 proteins share a common carboxyl region sequence. Chen et al. (1986) determined the complete cDNA and amino acid sequence of apoB100. Knott et al. (1986) reported the primary structure of apolipoprotein B. The precursor has 4,563 amino acids; the mature apoB100 has 4,536 amino acid residues. This represents a very large mRNA of more than 16 kb. Law et al. (1986) also provided the complete nucleotide acid and derived amino acid sequence of apoB100 from a study of cDNA. Strong evidence that apoB100 and apoB48 are products of the same gene was provided by Young et al. (1986). They used a specific mouse monoclonal antibody, MB19, to characterize a common form of genetic polymorphism of APOB. They found that the polymorphism was expressed in a parallel manner in apoB100 and apoB48.

Cladaras et al. (1986) concluded from the sequence of apolipoprotein B100 that apoB48 may result from differential splicing of the same primary apoB mRNA transcript. Hardman et al. (1987) found that mature, circulating B48 is homologous over its entire length (estimated to be between 2,130 and 2,144 amino acid residues) with the amino-terminal portion of B100 and contains no sequence from the carboxyl end of B100. From structural studies, Innerarity et al. (1987) concluded that apoB48 represents the amino-terminal 47% of apoB100 and that the carboxyl terminus of apoB48 is in the vicinity of residue 2151 of apoB100. Chen et al. (1987) deduced that human apolipoprotein B48 is the product of an intestinal mRNA with an in-frame UAA stop codon resulting from a C-to-U change in the codon CAA encoding Gln(2153) in apoB100 mRNA. The carboxyl-terminal ile-2152 of apoB48 purified from chylous ascites fluid has apparently been cleaved from the initial translation product, leaving met-2151 as the new carboxyl-terminus. The organ-specific introduction of a stop codon to an mRNA is an unprecedented finding. Only the sequence that codes B100 is present in genomic DNA. The change from CAA to UAA as codon 2153 of the message is a unique RNA editing process. Higuchi et al. (1988) reported similar findings. ApoB48 contains 2,152 residues compared to 4,535 residues in apoB100. Using a cloned rat cDNA as a probe, Lau et al. (1994) cloned cDNA and genomic sequences of the gene for the human APOB mRNA editing protein (BEDP; 600130). Expression of the cDNA in HepG2 cells resulted in editing of the intracellular apoB mRNA. By fluorescence in situ hybridization, they localized the BEDP gene to 12p13.2-p13.1. By Northern blot analysis, they showed that the human BEDP mRNA is expressed exclusively in the small intestine. The cDNA sequence predicted a translation product of 236-amino acid residues. They found that the editing protein undergoes spontaneous polymerization and exists as a dimer. The editing protein is a cytidine deaminase showing structural homology to other known mammalian and bacteriophage deoxycytidylate deaminases.

Steinberg et al. (1979) described a kindred with a new form of hypobetalipoproteinemia characterized by unusually low LDL cholesterol, normal triglyceride levels, low levels of HDL, mild fat malabsorption, and a defect in chylomicron clearance. On a high-carbohydrate diet, the triglyceride levels of the 67-year-old proband fell rather than rose. The proband, a retired Naval chaplain, was asymptomatic. He came to attention because of total serum cholesterol of 47 mg/dl. The proband's mother, aged 92, 1 brother, 1 sister, and 2 daughters also had hypobetalipoproteinemia. Young et al. (1987) found an abnormality of apoB, called apolipoprotein B37, in the plasma lipoproteins of multiple members of this kindred. Young et al. (1987) reported an intensive study of 41 members in 3 generations of this kindred. They documented the presence, in addition to the abnormal, truncated apoB species B37, of another apoB allele that was associated with reduced plasma concentrations of the normal apoB100. The proband (H.J.B.) and 2 of his sibs had both abnormal apoB alleles and were therefore compound heterozygotes for familial hypobetalipoproteinemia. All of the offspring of the 3 compound heterozygotes had hypobetalipoproteinemia, and each had evidence of only 1 of the abnormal apoB alleles. The average LDL cholesterol levels were: in the compound heterozygotes, 6 mg/dl; in the 6 heterozygotes who had only the abnormal apoB37 allele, 31 mg/dl; in the 10 heterozygotes who had only the allele for reduced plasma concentrations of apoB100, 31 mg/dl; and in 22 unaffected family members, 110 mg/dl.

Law et al. (1986) found that 60 of 83 middle-aged white men had an XbaI restriction site polymorphism within the coding sequence of the apoB gene. Persons homozygous or heterozygous for the XbaI restriction site had mean serum triglyceride levels 36% higher than homozygotes without the site. Mean serum cholesterol was less strikingly elevated in those with the restriction site. The Ag system of lipoprotein antigens (see later) is known to represent polymorphism of the APOB locus. It is in strong linkage disequilibrium with the XbaI RFLP; the 2 probably reveal the same association with plasma lipids. Mehrabian et al. (1986) also identified 2 common RFLPs which should be useful in family studies. Antonarakis (1987) and his colleagues identified a missense point mutation in the APOB gene associated with hyperbetalipoproteinemia. The mutation occurred at a potential site of binding of APOB to LDLR and apparently resulted in interference with the metabolism of apolipoprotein B. The finding of no recombination between the hypobetalipoproteinemia phenotype and a particular DNA haplotype of the APOB gene (Leppert et al., 1988) indicated that, at least in the family studied, hypobetalipoproteinemia was the result of a molecular defect in apolipoprotein B.

Singh et al. (2004) examined the association between the XbaI polymorphism of APOB100 and gallbladder diseases, including gallbladder cancer, in a non-Indian population in which both gallstones and gallbladder cancer are common. They found that the frequency of X- allele was significantly increased in gallbladder cancer patients with or without gallstones (odds ratio = 2.3 and 1.7, respectively). They suggested that the apoB-XbaI gene polymorphism confers susceptibility to carcinoma of the gallbladder under specific environmental conditions.

The base change in APOB that creates the XbaI site, 7673C-T, does not change the amino acid threonine at codon 2488 (T2488T). In a study comprising 9,185 individuals from the general population, 2,157 patients with ischemic heart disease (IHD), and 378 patients with ischemic cerebrovascular disease (ICVD), Benn et al. (2005) found that the APOB 7673C-T polymorphism is associated with moderate increases in total cholesterol, LDL cholesterol, and apoB in both genders in the general population, but not with risk of IHD or ICVD or with total mortality.

Benn et al. (2007) found that APOB K4154K homozygotes for the E4154K polymorphism had an age-adjusted hazard ratio of 0.4 (95% CI, 0.2-0.9) for ischemic cerebrovascular disease and 0.2 (CI, 0.1-0.7) for ischemic stroke relative to E4154E homozygotes. Furthermore, E4154K heterozygotes and K4154K homozygotes had lower levels of apolipoprotein B and LDL cholesterol, compared with E4154E homozygotes. APOB K4154K homozygosity predicted a 3- to 5-fold reduction in risk of ischemic cerebrovascular disease and ischemic stroke.

Keidar et al. (1990) described apparent compound heterozygosity for abetalipoproteinemia (200100) and familial hypobetalipoproteinemia. The finding indicated that abetalipoproteinemia may, like hypobetalipoproteinemia, be due to a mutation in the APOB gene. The proband, a 10-year-old boy with abetalipoproteinemia, had a father with a normal apolipoprotein profile; however, his mother and maternal grandfather suffered from familial hypobetalipoproteinemia. Talmud et al. (1988) presented evidence that the defect in abetalipoproteinemia (at least in the 2 families studied) does not involve the APOB gene: in each of these 2 families, 2 affected children inherited different APOB RFLP alleles from at least 1 parent, whereas the sibs would be anticipated to share common alleles if this disorder were due to an APOB mutation. Demant et al. (1988) found a significant association between a particular RFLP of the APOB gene and the total fractional clearance rate of LDL. Presumably, this effect acts through variable binding to the LDLR and is a significant factor in the rate of catabolism of LDL. Corsini et al. (1989) described familial hypercholesterolemia (FH) due, not to a defect in the LDLR as in conventional FH (143890), but to binding-defective LDL, presumably familial defective apoB100. Rajput-Williams et al. (1988) demonstrated association of specific alleles for the apoB gene with obesity, high blood cholesterol levels, and increased risk of coronary artery disease. Several of the RFLPs used as markers do not change the amino acid sequence. The authors concluded that these RFLPs are in linkage disequilibrium with nearby functional variation predisposing to obesity or increased risk of coronary artery disease. Variations in serum cholesterol level were associated with 3 functional alleles corresponding to amino acid variants at positions 3611 and 4154, both of which lie near the LDLR binding region of apoB. Products of the APOB gene with high or low affinity for the MB-19 monoclonal antibody can be distinguished. Gavish et al. (1989) used this antibody to identify heterozygotes and detect allele-specific differences in the amount of APOB in the plasma. A family study confirmed that the unequal expression phenotype was inherited in an autosomal dominant manner and was linked to the APOB locus.

Brown et al. (1974) noted that the consistent laboratory findings of reduced serum cholesterol and beta-lipoprotein define hypobetalipoproteinemia as a distinct syndrome. They found 4 reported kindreds and added a fifth. Only 2 of the patients in the reported families had symptoms. Mars et al. (1969) observed a family in which 1 of the 14 hypobetalipoproteinemic persons (in 3 generations), a 37-year-old woman, had signs and symptoms of progressive demyelination of the central nervous system, lack of responsiveness to local anesthesia, and dislike for animal fats and milk. The family reported by Brown et al. (1974) contained a child with psychomotor retardation. Although the peripheral blood smear showed no acanthocytes, the red cells on symptomatic and asymptomatic persons became acanthocytotic when placed in tissue culture medium with 10% autologous serum. Biemer and McCammon (1975) described a family and reviewed others in the literature in which a person with 'homozygous hypobetalipoproteinemia' had occurred. They pointed out that although some of these cases were milder than cases of abetalipoproteinemia, homozygous hypobetalipoproteinemia could often be distinguished from abetalipoproteinemia only by the demonstration of presumably heterozygous hypobetalipoproteinemic first-degree relatives of the homozygote. This may not indicate that these are determined by different loci; it may be a situation like the 3 probably allelic forms of cystinuria (220100) which are distinguishable only by whether amino aciduria is demonstrable in heterozygotes.

Kahn and Glueck (1978) reported remarkable freedom from atheroma in a 76-year-old woman who died from hepatic failure due apparently to hemochromatosis. The woman had been found to have hypobetalipoproteinemia in a study done previously (Glueck et al., 1976). This and hyperalphalipoproteinemia (143470) are accompanied by increased life expectancy.

Berger et al. (1983) studied a kindred in which the proband manifested the clinical and biochemical features of the homozygous state. Unlike the apparent absence of apolipoprotein B in the plasma in 5 previous cases of homozygous hypobetalipoproteinemia, they found a minute amount of apoB (about 0.025% of normal) in the plasma and suggested that the disorder might result not from a structural gene defect but from a failure of secretion. (McKusick (1983) stated that he would interpret this finding as supporting rather than refuting the structural mutation idea.) Since LDLs are a main source of cholesterol for steroid hormone formation, Parker et al. (1986) were interested in studying the endocrine changes during pregnancy in homozygous familial hypobetalipoproteinemia. They found it surprising that a woman with phenotypic abetalipoproteinemia, previously reported by Illingworth et al. (1979), could become 'pregnant, let alone carry the pregnancy to term without hormonal therapy.' They noted successful pregnancy in 3 other abetalipoproteinemic women. Harano et al. (1989) identified homozygous hypobetalipoproteinemia in 3 sibs. Both parents and 2 children of 1 of the sibs were heterozygous. The 75-year-old proband, the father of the 3 sibs, died of fever of unknown cause, thrombocytopenia, and anemia. He had ataxic movements of the hands and gait disturbance in later life. The 3 homozygotes showed marked deficiency of apoB100, although trace amounts were noted in LDL. In contrast, apoB48 was present in chylomicrons obtained after a fatty meal in 2 of the patients with homozygous hypobetalipoproteinemia, indicating a selective deficiency of apoB100. In 2 patients with homozygous hypobetalipoproteinemia, Ross et al. (1988) found that Southern blot analysis with 10 different cDNA probes revealed a normal gene without major insertions, deletions, or rearrangements. Northern and slot blot analyses of total liver mRNA showed a normal-sized apoB mRNA that was present in greatly reduced quantities. ApoB protein was detected in liver cells immunohistochemically but was markedly reduced in quantity, and no apoB was detectable in the plasma with an ELISA assay. Ross et al. (1988) interpreted the findings as indicating a mutation in the coding portion of the apoB gene, leading to an abnormal apoB protein and apoB mRNA instability. These findings were distinct from those previously noted in abetalipoproteinemia (200100), which is characterized by an elevated level of hepatic apoB mRNA and accumulation of intracellular hepatic apoB protein. The blood-lipid changes that accompany heterozygous hypobetalipoproteinemia are reduced plasma concentrations of LDL cholesterol, total triglycerides, and APOB to less than 50% of normal values. Leppert et al. (1988) found that a DNA haplotype of the APOB gene cosegregated with the phenotype in an Idaho pedigree, with a maximum lod score of 7.56 at theta = 0.0. This finding strongly suggests that a mutation in the APOB gene underlies hypobetalipoproteinemia and indicates the usefulness of the candidate gene approach. As indicated in the listing of allelic variants, a number of mutations resulting in a truncated apolipoprotein B have been found as the basis of hypobetalipoproteinemia. On the other hand, other patients with this disorder have been found to have reduced concentrations of a full-length apoB100 (Young et al., 1987; Berger et al., 1983; Gavish et al., 1989). This type of gene defect may prove to be analogous to beta(+)-thalassemia, which has been shown to be caused by promoter mutations, intron-exon splicing errors, or mutation in the polyadenylation signal. Araki et al. (1991) described a 55-year-old man with cerebellar ataxia due apparently to hypobetalipoproteinemia. A brother also had hypobetalipoproteinemia with neurologic symptoms. The 2 children of the proband, aged 31 and 29 years, and a sister of the proband had only hypobetalipoproteinemia. The proband and his neurologically affected brother as well as members of the 2 previous generations had steatocystoma multiplex (184500). The latter condition may have been coincidental.

Allison and Blumberg (1961) and Blumberg et al. (1963) described a polymorphic system including serum beta lipoprotein distinct from that discovered by Berg and Mohr and designated Lp(a) (see 152200). They detected this by the study of patients who had received multiple transfusions. The first type was called Ag-a; the second was called Ag-b. Blumberg et al. (1964) proposed the symbol LP for lipoprotein. Lower case letters are used for designating different loci (i.e., LPa, LPb, LPc, etc.) and superscript numbers for alleles at the locus (i.e., LPa-1, LPa-2, etc.). Retention of the Ag designation may be advisable to avoid confusion with the Berg type. Jackson et al. (1974) observed a family in which variation of a chromosome 21 appeared to be linked with Ag type. The peak lod score was 2.1 at a recombination fraction of 0.0. Berg et al. (1975), on the other hand, found considerable recombination with IPO-A (147450), in family studies. IPO-A is known to be on chromosome 21 from hybrid cell studies. Berg et al. (1976) showed that serum cholesterol and triglyceride levels were higher in Ag(x-) than in Ag(x+) persons. Thus, a small but significant effect of a single autosomal locus in atherogenesis may have been demonstrated. Morganti et al. (1975) indicated that there are at least 5 closely linked loci. This serum protein polymorphism was discovered by Blumberg on the basis of his hypothesis that multitransfused patients should have antibodies against polymorphic serum proteins. The Australia antigen was found in the process of the same studies, applying the additional principle that the wider the anthropologic spread of sera tested (e.g., Australian aborigines), the greater the likelihood of finding a polymorphism. Of course, the Australia antigen proved to be not a polymorphism but a viremia--an even more important discovery, as recognized by the Nobel Prize. By this approach, Blumberg (1978) found other apparent polymorphisms that he has not yet fully studied. Allotypic variation in LDL comparable to Ag has been found in most species studied. Berg et al. (1986) demonstrated close linkage of the Ag allotypes of LDL and DNA polymorphisms at the APOB locus. Linkage disequilibrium (allelic association) was found between the Ag polymorphism and 2 of the 3 DNA polymorphisms studied. Xu et al. (1989) demonstrated that a particular Ag epitope (h/i) is determined by an arginine-to-glutamine substitution at residue 3611 of the mature protein. The amino acid difference results from a CGG-to-CAG change and causes loss of an MspI restriction site. Breguet et al. (1990) found that, with the exception of the Amerindians, the Ag system is highly polymorphic in populations worldwide. They suggested that the system has evolved as a neutral or nearly-neutral polymorphism and is therefore highly informative for 'modern human peopling history' studies. Following the cloning of the human APOB gene, nucleotide substitutions were reported as candidates for the molecular basis of all the Ag epitopes (reviewed by Dunning et al., 1992). Dunning et al. (1992) found complete linkage disequilibrium between the immunochemical polymorphism of LDL that is designated antigen group Ag(x/y) and the alleles at 2 sites in the mature apoB100 molecule: pro2712-to-leu and asn4311-to-ser. It appeared that the Ag(y) epitope was associated with asparagine-4311 plus proline-2712, whereas the allele encoding serine-4311 plus leucine-2712 represented the Ag(x) epitope. In 4 different population groups, they found complete association between the sites encoding residues 2712 and 4311, although there were large allele frequency differences between these populations. In addition, there was strong linkage disequilibrium with allelic association between the alleles of these sites and those of the XbaI RFLP in all populations examined. Taken together, these data suggest that there has been little or no recombination in the 3-prime end of the human APOB gene since the divergence of the major ethnic groups.

Ludwig et al. (1989) described a hypervariable region 3-prime to the human APOB gene. By PCR amplification of the region followed by electrophoresis in a denaturing acrylamide gel, they found 14 different alleles containing 25 to 52 repeats of a 15-basepair unit in 318 unrelated individuals. Boerwinkle et al. (1989) also made observations on this variable-number-of-tandem-repeats (VNTR) polymorphism. Boehnke (1991) used the VNTR polymorphism near the APOB locus as a test case for his method of estimating allele frequency from data on relatives. He stated that there are 15 known APOB VNTR alleles and that 12 were observed in the families he studied. By use of both pedigree linkage analysis and sib-pair linkage analysis in 23 informative families, Coresh et al. (1992) found no evidence of common APOB alleles that had a major influence on plasma levels of apoB100.

Familial hypocholesterolemia can be caused not only by defects in the LDL receptor (LDLR; 606945) but also by mutations in apolipoprotein B causing decreased LDLR binding affinity, so-called familial ligand-defective apolipoprotein B. The first mutation of this sort was described by Soria et al. (1989); see 107730.0009. A second was described by Pullinger et al. (1995); see 107730.0017.

Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988). Linton et al. (1993) tabulated 25 apoB gene mutations associated with familial hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is an autosomal dominant disorder of lipid metabolism characterized by extremely low plasma levels of apolipoprotein B, as well as low levels of total- and low-density lipoprotein (LDL) cholesterol. Pulai et al. (1998) commented that various truncated forms of apoB have been found to segregate with the FHBL phenotype in more than 30 kindreds. They reported studies of 6 kindreds in which no truncated forms of apoB protein were detected with sensitive immunoblotting in the plasmas of any of the affected individuals. Persons with apoB levels in the fifth centile for their age and sex were considered as affected with FHBL. Linkage analysis with 3 microsatellite markers flanking the APOB gene, a 3-prime VNTR marker, and an intragenic marker yielded 2-point linkage of FHBL to the 3-prime VNTR marker with a combined maximum lod score of 8.5 at theta = 0.0 for 5 of the 6 families. A test of homogeneity differentiated the sixth family from the other 5. These kindreds demonstrated the heterogeneity of FHBL and also offered the possibility to investigate as yet undescribed mutations of APOB, resulting in alterations of apoB metabolism. The unlinked kindred may shed light on a novel gene contributing to the low apoB phenotype; see FHBL2 (605019).

Schonfeld (1998) stated that in all reported kindreds in which the 'hypobeta' trait cosegregated with an apoB truncation, heterozygotes (documented by either protein or genomic DNA analysis) showed the trait. In fasting heterozygotes, there are 2 populations of apoB-containing lipoproteins: those that contain the truncation and those that contain the normal full-length apoB100. The low cholesterol levels are due to the low levels of apoB-containing lipoproteins (VLDL and particularly LDL) that transport most of the cholesterol in plasma. In turn, low levels of apoB are due to low production rates of both mutant and wildtype forms of apoB in heterozygotes. In some cases, there is also enhanced clearance from plasma. Low production of a truncated form is probably due to low levels of the truncation-specifying mRNA. It is not clear why wildtype apoB100 is produced at lower than expected rates in heterozygotes.

Kairamkonda and Dalzell (2003) described 3 sibs with vitamin E deficiency and symptoms of malabsorption with documented excessive fecal fat excretion and low cholesterol, apoB, and vitamin E levels. Although the pathogenesis was not established, the authors postulated that the sibs had heterozygous FHBL due to a novel mutation of apoB because of persistent posttherapeutic low cholesterol and apoB levels.

Di Leo et al. (2007) identified 3 novel splice site mutations of the APOB gene in 4 FHBL patients and analyzed apoB mRNA in the liver of 1 proband and in transfected COS1 cells in the other probands. The authors determined that all 3 mutations resulted in truncated apoB proteins that were not secreted as constituents of plasma lipoproteins, confirming the pathogenic effect of rare splice site mutations of the APOB gene found in FHBL.

Di Leo et al. (2008) reported 3 patients with severe hypobetalipoproteinemia due to homozygosity or compound heterozygosity for mutations in APOB, who presented with chronic liver disease and/or chronic diarrhea at ages 52, 55, and 19 years, respectively. The authors stated that the clinical diagnosis of homozygous FHBL is extremely rare, with approximately 20 cases reported over the past 2 decades; they noted that their patients highlight the heterogeneity of clinical manifestations and the possible presentation of disease late in life.

Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs693 of APOB, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.

Teslovich et al. (2010) performed a genomewide association study for plasma lipids in more than 100,000 individuals of European ancestry and reported 95 significantly associated loci (P = less than 5 x 10(-8)), with 59 showing genomewide significant association with lipid traits for the first time. The newly reported associations included SNPs near known lipid regulators as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contributed not only to normal variation in lipid traits but also to extreme lipid phenotypes and had an impact on lipid traits in 3 non-European populations (East Asians, South Asians, and African Americans). Teslovich et al. (2010) identified several novel loci associated with plasma lipids that are also associated with coronary artery disease. Teslovich et al. (2010) identified rs1367117 in the APOB gene as having an effect on LDL cholesterol with an effect size of +4.05 mg per deciliter and a P value of 4 x 10(-114).

In a 27-year-old woman from a consanguineous French Canadian family, who was diagnosed with FHBL in the first months of life, Gangloff et al. (2011) identified a homozygous truncating mutation in the APOB gene (107730.0022). The authors stated that this was the first case of homozygous FHBL in a French Canadian family.

Animal Model

Rapacz et al. (1986) described a strain of pigs bearing 3 immunogenetically defined lipoprotein-associated markers (allotypes) associated with marked hypercholesterolemia despite a low-fat, cholesterol-free diet. LDL receptor activity was normal. By 7 months of age the animals had extensive atherosclerotic lesions in all 3 coronary arteries. One of the 3 variant apolipoproteins was apolipoprotein B. The identity of the other 2 apolipoproteins was not clear, although one was a component of low density lipoprotein and was genetically linked to the variant identified with apolipoprotein B.

Homanics et al. (1993) used gene targeting to generate a mouse model of hypobetalipoproteinemia. Mice carrying the disrupted Apob gene synthesized apoB48 and a truncated apoB (apoB70) but no apoB100. In addition to having a lipoprotein phenotype remarkably similar to familial hypobetalipoproteinemia in humans, these mice also exhibited exencephalus and hydrocephalus. Huang et al. (1995) likewise generated APOB gene knockout mice by targeting the gene in embryonic stem cells. Homozygous deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some liveborn heterozygotes developing hydrocephalus. Most heterozygous males were sterile, although the GU system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total LDL and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal APOB mRNA levels were decreased in heterozygotes.

Callow et al. (1995) noted that the engineering of mice that express a human APOB transgene results in animals with high levels of human-like LDL particles. Additionally, through crosses with transgenics for the human LPA gene, high levels of human-like lipoprotein(a) particles are seen. Callow et al. (1995) found that such mice demonstrated marked increases in apoB and LDL, resulting in atherosclerotic lesions extending down the aorta that resembled human lesions immunochemically. The findings suggested to the authors that APO(a) associated with apo(B) and lipid may result in a more pro-atherogenic state than when APO(a) is free in plasma.

Huang et al. (1996) found that male mice heterozygous for targeted mutation of the ApoB gene exhibit severely compromised fertility. Sperm from these mice fail to fertilize eggs both in vitro and in vivo. However, these sperm were able to fertilize eggs once the zona pellucida was removed but displayed persistent abnormal binding to the egg after fertilization. In vitro fertilization-related and other experiments revealed reduced sperm motility, survival time, and sperm count also contributed to the infertility phenotype. Recognition of the infertility phenotype led to the identification of ApoB mRNA in the testes and epididymides of normal mice, and these transcripts were substantially reduced in the mutant animal. Moreover, when the genomic sequence encoding human ApoB was introduced into these animals, normal fertility was restored. The findings of Huang et al. (1996) suggested that the APOB locus may have an important impact on male fertility and identified a previously unrecognized function of ApoB.

To provide models for understanding the physiologic purpose for the 2 forms of apoB (B100 and B48), Farese et al. (1996) used targeted mutagenesis of the APOB gene to generate mice that synthesized apoB48 exclusively and mice that synthesized apoB100 exclusively. The B48-only and B100-only mice were produced by introducing into mouse ES cells stop and nonstop mutations, respectively, in the apoB48 editing codon (codon 2153) of the mouse Apob gene. Both types of mice developed normally, were healthy, and were fertile. Thus, apoB48 synthesis sufficed for normal embryonic development, and the synthesis of apoB100 in the intestine adult mice caused no readily apparent adverse effects on intestinal function or nutrition. Compared with wildtype mice fed the same diet, the levels of LDL cholesterol and VLDL and LPL triacylglycerols were lower in the B48-only mice and higher in the B100-only mice. Farese et al. (1996) stated that in the setting of apo-E deficiency, the B100-only mutation lowered cholesterol levels, consistent with the fact that B100-lipoproteins can be cleared from the plasma via the LDL receptor, whereas B48-lipoproteins lacking apo-E cannot.

Boren et al. (1998) expressed mutant forms of human apoB in transgenic mice, purified the resulting human recombinant LDL, and tested for their receptor-binding activity. They showed that amino acids 3359 to 3369 bind to the LDL receptor and that arginine-3500 is not directly involved in receptor binding. However, the C-terminal 20% of apoB100 is necessary for the R3500Q mutation to disrupt receptor binding, since removal of the C terminus in familial defective apoB100 (FDB) LDL resulted in normal receptor-binding activity. Similarly, removal of the C terminus of apoB100 on receptor-inactive VLDL dramatically increased apoB-mediated receptor-binding activity. Boren et al. (1998) proposed that the C terminus normally functions to inhibit the interaction of apoB100 VLDL with the LDL receptor, but after the conversion of triglyceride-rich VLDL to smaller cholesterol-rich LDL, arginine-3500 interacts with the C terminus, permitting normal interaction between LDL and its receptor. Moreover, the loss of arginine at this site destabilizes this interaction, resulting in receptor-binding defective LDL.

Skalen et al. (2002) created transgenic mice expressing 5 types of human recombinant LDL, fed them an atherogenic diet for 20 weeks, and quantitated the extent of atherosclerosis. They used these models to test the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively-charged sulfate groups on the proteoglycans. Skalen et al. (2002) presented direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wildtype control LDL. Skalen et al. (2002) concluded that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.

In order to demonstrate the therapeutic potential of short interfering RNAs (siRNAs), Soutschek et al. (2004) demonstrated that chemically modified siRNAs can silence an endogenous gene encoding apoB after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB mRNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. Soutschek et al. (2004) also showed that these siRNAs could silence human apoB in a transgenic mouse model. In their in vivo study, the mechanism of action for the siRNAs was proven to occur through RNA interference (RNAi)-mediated mRNA degradation, and Soutschek et al. (2004) determined that cleavage of the apoB mRNA occurred specifically at the predicted site.

Espinosa-Heidmann et al. (2004) studied the development of basal laminar deposits in the eyes of transgenic mice that overexpressed apoB100. The mice were fed a high-fat diet, and their eyes were exposed to blue-green laser light. The results suggested that age and high-fat diet predisposed to the formation of basal laminar deposits by altering hepatic and/or retinal pigment epithelial lipid metabolism in ways more complicated than plasma hyperlipidemia alone. Vitamin E-treated mice showed minimal formation of basal laminar deposits.

In the eyes of transgenic mice overexpressing human apoB100 in the RPE, Fujihara et al. (2009) observed ultrastructural changes consistent with early human age-related macular degeneration (ARMD) (see 603075), including loss of basal infoldings and accumulation of cytoplasmic vacuoles in the RPE and basal laminar deposits containing long-spacing collagen and heterogeneous debris in Bruch membrane. In apoB100 mice given a high-fat diet, basal linear-like deposits were identified in 12-month-old mice. Linear regression analysis showed that the genotype was a stronger influencing factor than high-fat diet in producing ARMD-like lesions.

ALLELIC VARIANTS (Selected Examples):

Table View

.0001 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, ASN1728THR AND SER1729TER

In a patient with hypobetalipoproteinemia and small amounts of truncated protein (B37) in VLDL, LDL, and HDL fractions of the plasma, Young et al. (1987, 1988) found deletion of nucleotides 5391-5394 resulting in a frameshift causing change of asn1728 to thr and ser1729 to stop. The truncated apoB protein contained 1,728 amino acids. This was one of the mutant alleles in the family with hypobetalipoproteinemia first reported by Steinberg et al. (1979). Linton et al. (1992) investigated the reason for the curious finding that low levels of apoB100 were produced by the mutant allele carrying this mutation. The clue that led to the understanding of what was going on with this allele was the recognition that the proband in the family, H.J.B., as well as the other 2 compound heterozygotes, actually had 4 bona fide apoB species within their plasma lipoproteins: apoB37, apoB48, apoB100, and apoB86. Linton et al. (1992) demonstrated that the apoB86 and apoB100 were products of a single mutant apoB allele, which they designated the apoB86 allele. They showed that this allele has a 1-bp deletion in exon 26 of the APOB gene and that this frameshift is responsible for the synthesis of apoB86. Nevertheless, as shown by cell culture expression studies, the apoB86 allele, which contains a premature stop codon, results in the synthesis of a full-length apoB protein. The 1-bp deletion creates a stretch of 8 consecutive adenines. Addition of a single adenine within the 8 consecutive adenines appears to take place during transcription, restoring the correct reading frame and accounting for the formation of apoB100 by the apoB86 allele. Eleven percent of the cDNA clones had an additional adenine within the stretch of 8 adenines.

.0002 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB39

APOB39

APOB, 1-BP DEL, FS1799TER

Collins et al. (1988) described a truncated apoB protein due to deletion of a single guanine nucleotide from leucine codon 1794, resulting in a frameshift and a stop codon after codon 1799. The truncated protein was referred to as apoB39. The mutation occurred in a CpG dinucleotide.

.0003 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, ARG1306TER [dbSNP:rs121918383]

A second truncated variant of apoB found in hypobetalipoproteinemia by Collins et al. (1988) had a change of arginine codon 1306, converting it to a stop codon and resulting in a protein of 1,305 residues which, however, could not be detected in the circulation. This mutation was a C-to-T transition in a CpG dinucleotide.

.0004 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB40

APOB40

APOB, VAL1829CYS [dbSNP:rs121918384]

Krul et al. (1989) found 2 distinct truncated apoB proteins, apoB40 and apoB90, in a kindred with hypobetalipoproteinemia. Talmud et al. (1989) showed that the molecular basis was deletion of 2 nucleotides converting val1829 to cys and codon 1830 to stop.

.0005 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB90 OR APOB89

APOB90/APOB89

APOB, GLU4034ARG [dbSNP:rs121918385]

See Krul et al. (1989). The molecular basis was deletion of 1 nucleotide in glutamic acid codon 4034 converting that codon to arginine and causing a frameshift with a stop codon at position 4040 (Talmud et al., 1989). Parhofer et al. (1992) showed that enhanced catabolism of VLDL, IDL, and LDL particles containing the truncated apolipoprotein is responsible for the relatively low levels of apoB89 seen in these subjects.

.0006 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB46

APOB46

APOB, ARG2058TER [dbSNP:rs121918386]

Young et al. (1989) characterized an apoB gene mutation in a kindred with familial hypobetalipoproteinemia. Six members of the family had low plasma apoB and LDL cholesterol levels, and each was shown to be heterozygous for a mutant apoB allele that yielded a unique truncated species of apoB, namely apoB46, with only 2,037 amino acids. They further showed that apoB46 is caused by the substitution of T for C at apoB cDNA nucleotide 6381, resulting in a nonsense mutation. The change occurred in a CG dinucleotide. A C-to-T transition in the APOB gene was responsible for hypobetalipoproteinemia in one of the families studied by Collins et al. (1988). Like CETP deficiency (143470), this appears to be an antiatherogenic mutation.

.0007 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB87

APOB87

APOB

Young et al. (1990) referred to a truncated apoB species, apoB87, on the basis of their unpublished work.

.0008 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB31

APOB31

APOB, 1-BP DEL, 1425G

Young et al. (1990) identified a mutation of the APOB gene that resulted in formation of a truncated apoB species, apoB31. The mutation consisted of deletion of a single guanine residue which caused a frameshift and a premature termination with formation of a protein predicted to contain 1,425 amino acids. This is the shortest of the mutant apoB species identified in the plasma of subjects with hypobetalipoproteinemia. In contrast to the longer truncated proteins, apoB31 was undetectable in VLDL and LDL but was present in the HDL fraction and in the lipoprotein-deficient fraction of the plasma. This mutation was found in the course of studying the apoB46 mutant (Young et al., 1989).

.0009 HYPERCHOLESTEROLEMIA DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B100

APOB, ARG3500GLN [dbSNP:rs5742904]

Vega and Grundy (1986) showed that some patients with hypercholesterolemia (143890) have reduced clearance of LDL not because of decreased activity of LDL receptors but because of a defect in the structure (or composition) of LDL that reduces its affinity for receptors. In 5 of 15 patients, turnover rates indicated that clearance of autologous LDL was significantly lower than for homologous normal LDL. In these 5 patients, autologous LDL appeared to be a poor ligand for LDL receptors. The authors did not carry the investigations far enough to determine whether abnormality in the primary structure of apoB100 accounted for the poor binding to receptors. Innerarity et al. (1987) found that moderate hypercholesterolemia could be attributed to defective receptor binding of a genetically altered apoB100 to the LDL receptor. A finding of the same abnormality in several of the proband's first-degree relatives indicated the inherited nature of the defect. The proband of the family studied by Innerarity et al. (1987) was described earlier by Vega and Grundy (1986). This disorder was referred to as familial defective apolipoprotein B100 (144010).

Weisgraber et al. (1988) found an antibody, whose isotope is between residues 3350 and 3506 of apoB, that distinguishes abnormal LDL from normal LDL in this disorder; the antibody MB47 bound with a higher affinity to abnormal LDL. Thus, an assay was provided for screening large populations for this disorder. Illingworth et al. (1992) found that LDL cholesterol was reduced after administration of lovastatin in 12 hypercholesterolemic patients from 10 unrelated families with familial defective apoB100.

By extensive sequence analysis of the 2 alleles of the APOB gene of a subject heterozygous for familial defective apolipoprotein, Soria et al. (1989) demonstrated a mutation in the codon for amino acid 3500 that results in the substitution of glutamine for arginine. This same mutant allele was found in 6 other, unrelated subjects and in 8 affected relatives in 2 of these families. A partial haplotype of this mutant apoB100 allele was constructed by sequence analysis and restriction enzyme digestion at positions where variations in the apoB100 are known to occur. This haplotype was found to be the same in 3 probands and 4 affected members of 1 family and lacks a polymorphic XbaI site whose presence has been correlated with high cholesterol levels. Thus, it appears that the mutation in the codon for amino acid 3500 (CGG-to-CAG), a CG mutation hotspot, defines a minor apoB100 allele associated with defective low density lipoproteins and hypercholesterolemia. Ludwig and McCarthy (1990) used 10 markers for haplotyping at the APOB locus in cases of familial defective apolipoprotein B100: 8 diallelic markers within the structural gene and 2 hypervariable markers flanking the gene. In 14 unrelated subjects heterozygous for the mutation, 7 of 8 unequivocally deduced haplotypes were identical, and 1 revealed only a minor difference at one of the hypervariable loci. The genotypes of the other 6 affected subjects was consistent with the same haplotype. Familial defective apolipoprotein B100 (FDB) results from a G-to-A transition at nucleotide 10708 in exon 26 of the APOB gene. Ludwig and McCarthy (1990) interpreted the data as consistent with the existence of a common ancestral chromosome. In a screening for the APOB3500 mutation by PCR amplification and hybridization with an allele-specific oligonucleotide, Loux et al. (1993) found only 1 case among 101 French subjects with familial hypercholesterolemia. The son of this individual, a 45-year-old man, was found also to have the mutation. Haplotype analysis revealed strict identity to that previously reported by Ludwig and McCarthy (1990), thus supporting a unique European ancestry. The family lived in the southwest of France and had no knowledge of Germanic origin.

Rauh et al. (1992) stated that the frequency of the arg3500-to-gln mutation has been found to be approximately 1/500 to 1/700 in several Caucasian populations in North America and Europe. On the other hand, Friedlander et al. (1993) found no instance of this mutation in a large screening program in Israel. They pointed out that the mutation has also not been found in Finland (Hamalainen et al., 1990) and is said to be absent in Japan. Tybjaerg-Hansen and Humphries (1992) gave a review suggesting that the risk of premature coronary artery disease in the carriers of the mutation is increased to levels as high as those seen in patients with familial hypercholesterolemia; at age 50, about 40% of males and 20% of females heterozygous for the mutation have developed coronary artery disease.

Marz et al. (1992) found only moderate hypercholesterolemia in a 54-year-old man who was homozygous for the arg3500-to-gln mutation and on a normal diet without lipid-lowering medication. There was no evidence of atherosclerosis and no history of cardiovascular complaints. The levels of apoE-containing lipoproteins were normal. Marz et al. (1992) suggested that the intact metabolism of apoE-containing particles decreases LDL production in this disorder, explaining the difference from familial hypercholesterolemia due to a receptor defect in which apoE levels are raised. Marz et al. (1993) investigated possible compensatory mechanisms that may have alleviated the consequences of the familial defective apoB100 (FDB). They showed that the receptor interaction of buoyant LDL is normal due to the presence of apoE in these particles. In addition, they provided evidence that the arg3500-to-gln substitution profoundly alters the conformation of the apoB receptor binding domain when apolipoprotein B resides on particles at the lower and upper limits of the LDL density range. They concluded that these mechanisms distinguish FDB from FH and account for the mild hypercholesterolemia in homozygous FDB. Among 43 patients with clinically and biochemically defined type III hyperlipoproteinemia (107741), Feussner and Schuster (1992) found no instance of the arg3500-to-gln mutation.

In the course of investigating the reason that 2 unrelated French patients heterozygous for mutations in the LDLR gene had aggravated hypercholesterolemia, Benlian et al. (1996) found that each carried the identical arg3500-to-gln mutation in the APOB gene, i.e., were double heterozygotes. One of the patients was a 10-year-old boy when he was referred for hypercholesterolemia discovered at the time of a cardiac arrest. He had no planar xanthomata, although he exhibited bilateral xanthomas of the Achilles and metacarpal phalangeal tendons. Peripheral arterial disease was demonstrated by the presence of arterial murmurs and by arterial wall irregularity on ultrasound analysis. Stenoses of coronary arteries necessitated surgical angioplasty. The second patient was a 39-year-old man with myocardial infarction and acute ischemia of the legs. Both families came from the Perche region from which many French Canadians originated. The LDLR mutations trp66-to-gly (606945.0003) and glu207-to-lys (606945.0007) had been previously described in French Canadians. Rubinsztein et al. (1993) described an Afrikaner family with 6 FH/FDB double heterozygotes carrying another LDLR mutation, asp206-to-glu (606945.0006). (Benlian et al. (1996), in the title of their article, correctly referred to these patients as double heterozygotes; in the paper itself they incorrectly referred to them as FH/FDB compound heterozygotes. The latter term is used for heterozygosity for alleles at the same locus.)

In a patient homozygous for the R3500Q mutation, Schaefer et al. (1997) found LDL cholesterol and apoB concentrations approximately twice normal, whereas apoE plasma level was low. Using a stable-isotope labeling technique, they obtained data showing that the in vivo metabolism of apoB100-containing lipoproteins in FDB is different from that in familial hypercholesterolemia, in which LDL receptors are defective. Although the residence times of LDL apoB100 appeared to be increased to approximately the same degree, LDL apoB100 synthetic rate was increased in FH and decreased in FDB. The decreased production of LDL apoB100 in FDB may originate from enhanced removal of apoE-containing LDL precursors by LDL receptors, which may be upregulated in response to the decreased flux of LDL-derived cholesterol into hepatocytes.

Almost all individuals with familial defective apoB100 are of European descent, and in almost all cases the mutation is on a chromosome with a rare haplotype at the apoB locus, suggesting that all probands are descended from a common ancestor in whom the original mutation occurred. Distribution of the mutation is consistent with an origin in Europe 6,000 to 7,000 years ago. Myant et al. (1997) estimated the amount of recombination between the APOB gene and markers on chromosome 2 in 34 FDB (R3500Q) probands in whom the mutation is on the usual 194 haplotype. Significant linkage disequilibrium was found between the APOB gene and marker D2S220. They identified 3 YACs that contained the APOB gene and D2S220. The shortest restriction fragment common to the 3 YACs that contain both loci was 240 kb long. No shorter fragments with both loci were identified. On the assumption that 1000 kb corresponds to 1 cM, Myant et al. (1997) deduced that the recombination distance between D2S220 and the APOB gene is about 0.24 cM. Combining this value with the linkage disequilibrium observed between the 2 loci in the probands, they estimated that the ancestral mutation occurred about 270 generations ago. They postulated that the original mutation occurred in the common ancestor of living FDB (R3500Q) probands, who lived in Europe about 6,750 years ago.

Tybjaerg-Hansen et al. (1998) found that the R3500Q mutation in the APOB gene is present in approximately 1 in 1,000 persons in Denmark and causes severe hypercholesterolemia and increases the risk of ischemic heart disease. Heterozygous carriers of the arg3531-to-cys (107730.0017) mutation, which is present in the population in approximately the same frequency and also is associated with familial defective apolipoprotein B100, was not associated with higher-than-normal plasma cholesterol levels or an increased risk of ischemic heart disease.

Saint-Jore et al. (2000) estimated the respective contributions of the LDLR gene defect, APOB gene defect, and other gene defects in autosomal dominant type IIa hypercholesterolemia by studying 33 well-characterized French families in which this disorder had been diagnosed over at least 3 generations. Using the candidate gene approach, they found that defects in the LDLR gene accounted for the disorder in about 50% of the families. The estimated contribution of an APOB gene defect was only 15%. This low estimation of involvement of the APOB gene defect was strengthened by the existence of only 2 probands carrying the R3500Q mutation. Surprisingly, 35% of the families were estimated to be linked to neither LDLR nor APOB. The results suggested that genetic heterogeneity in type IIa hypercholesterolemia had been underestimated and that at least 3 major groups of defects were involved. The authors were unable to estimate the contribution of the FH3 gene (603776).

Boren et al. (2001) concluded that normal receptor binding of LDL involves an interaction between arginine-3500 and tryptophan-4369 in the carboxyl tail of apoB100. Trp4369 to tyr (W4369Y) LDL and arg3500 to gln (R3500Q) LDL isolated from transgenic mice had identically defective LDL binding and a higher affinity for a monoclonal antibody that has an epitope flanking residue 3500. Boren et al. (2001) concluded that arginine-3500 interacts with tryptophan-4369 and facilitates the conformation of apoB100 required for normal receptor binding of LDL. They developed a model that explained how the carboxyl terminus of apoB100 interacts with the backbone of apoB100 that enwraps the LDL particle. The model explained how all known ligand-defective mutations in apoB100, including a newly discovered R3480W mutation, cause defective receptor binding.

Horvath et al. (2001) studied 130 unrelated individuals with hypercholesterolemia in Bulgaria. Four of these individuals were found to be carriers of this mutation. Horvath et al. (2001) concluded that this mutation accounts for 0.99 to 8.17% (95% CI) of cases of hypercholesterolemia in Bulgaria and therefore represents the most common single mutation associated with this condition in Bulgaria.

Bednarska-Makaruk et al. (2001) found the arg3500-to-gln mutation in 2.5% (13/525) of unrelated patients with hypercholesterolemia in Poland. All the patients belonged to the type IIA hyperlipoproteinemia group. In 65 patients with the clinical characteristics of familial hypercholesterolemia, the frequency of the arg3500-to-gln mutation was 10.8% (7/65). The same haplotype at the APOB locus in the carriers of this mutation in Poland as in other populations from western Europe suggested its common origin.

.0010 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, EX21DEL

In an Arab patient with hypobetalipoproteinemia and absent plasma apolipoprotein B, Huang et al. (1989) demonstrated deletion of the entire exon 21 (211 basepairs coding for amino acids 1014 to 1084).

.0011 APOB POLYMORPHISM IN SIGNAL PEPTIDE

APOB, INS AND DEL

Visvikis et al. (1990) described an insertion/deletion polymorphism in the signal peptide. One allele, coding a peptide 27 amino acids long, had a frequency of 0.655; the second allele, coding a peptide 24 amino acids long, had a frequency of 0.345.

.0012 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, LEU3041TER [dbSNP:rs121918387]

In a man with hypobetalipoproteinemia and 6 of his 12 children, Welty et al. (1991) found that the plasma lipoproteins contained a unique species of apolipoprotein B, apoB67, in addition to the normal species, apoB100 and apoB48. Further study indicated that the apoB67 was a truncated species that contained approximately the amino-terminal 3,000 to 3,100 amino acids of apoB100. Heterozygosity was identified for a mutant APOB allele containing a single nucleotide deletion in exon 26 (cDNA nucleotide 9327). The change in codon 3041 from ATA (leu) to TAG (stop) led to truncation after amino acid 3040. Mean total and LDL cholesterol levels were 120 and 42 mg/dl, respectively. All affected members of the kindred had high HDL cholesterol levels.

.0013 HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC

APOB, GLN2252TER [dbSNP:rs121918388]

Malloy et al. (1981) described a patient (A.F.) with a metabolic disorder they termed normotriglyceridemic abetalipoproteinemia. Similar cases were reported by Takashima et al. (1985), Herbert et al. (1985), and Harano et al. (1989). The disorder was characterized by the absence of LDLs and apoB100 in plasma with apparently normal secretion of triglyceride-rich lipoproteins containing apoB48. Subsequent studies in A.F. suggested that the patient's plasma might be a truncated form of apoB100, slightly longer than the normal apoB48 chain. Hardman et al. (1991) demonstrated that the patient was homozygous for a single C-to-T substitution at nucleotide 6963 of apoB cDNA. This substitution resulted in a change from CAG (glutamine) to TAG (stop) at position 2252. Thus, this was a rare example of homozygous hypobetalipoproteinemia. Because LDL particles that contained apoB50 lacked the putative ligand domain of the LDL receptor, the very low level of LDL was presumably due to the rapid removal of the abnormal VLDL particles before their conversion to LDL could take place. As reviewed by Hardman et al. (1991), a considerable number of mutations resulting in truncated versions of apoB have been described, the smallest variant being apoB31, and the longest, apoB90. Using 3 genetic markers of the APOB gene in a study of the family reported by Takashima et al. (1985), Naganawa et al. (1992) found that the proband and her affected brother showed completely different APOB alleles, indicating that in this family the defect was not in the APOB gene.

Homer et al. (2005) suggested that the term 'normotriglyceridemic hypobetalipoproteinemia' is preferred to 'normotriglyceridemic abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers to the disorder caused by mutation in the MTP gene (157147).

.0014 HYPOBETALIPOPROTEINEMIA, FAMILIAL, ASSOCIATED WITH APOB32

APOB32

APOB, GLN1450TER [dbSNP:rs121918389]

In a person with heterozygous hypobetalipoproteinemia, McCormick et al. (1992) identified a nonsense mutation, gln1450-to-ter that prevented full-length translation. The new apolipoprotein B, apoB32, is predicted to contain the 1,449 amino-terminal amino acids of apoB100. It was associated with a markedly decreased level of low density lipoprotein (LDL cholesterol). Unique among the truncated apoB species, apoB32 was found in the high density lipoprotein and lipoprotein-depleted fractions, suggesting that it was mainly assembled into abnormally dense lipoprotein particles.

.0015 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, ARG2495TER [dbSNP:rs121918390]

Talmud et al. (1992) identified a C-to-T transition at nucleotide 7692 of the APOB gene which changed the CGA arginine codon to a stop codon resulting in a premature termination of apoB100. The truncated protein was predicted to be 2,494 amino acids long with the predicted size of apoB55. The patient had low total cholesterol and LDL-cholesterol as did also other relatives in an autosomal dominant pattern. In addition, the propositus, his mother, and both of his sibs had atypical retinitis pigmentosa. Since the RP-affected brother did not have the APOB mutation, Talmud et al. (1992) concluded that the eye disease was independent of the hypobetalipoproteinemia. They speculated, however, that a reduction in apoB-containing lipoproteins might alter the balance of the fatty acid supply to the retina and thus affect the evolution of retinitis pigmentosa in this family. The retinitis pigmentosa was late in onset.

.0016 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, 1-BP DEL

In H.J.B. and 2 sibs with asymptomatic familial hypobetalipoproteinemia reported by Steinberg et al. (1979), Linton et al. (1992) demonstrated that one of the alleles, which yielded very low levels of apoB100, had a deletion of a single cytosine in exon 26 (nucleotide 11840 of the apoB cDNA). This frameshift mutation was predicted to yield a 20-amino acid sequence (KKQIMLKQSWIPHAAQPYSS) not found in the wildtype, followed by a premature stop codon. Indeed, they found an antiserum to a synthetic peptide containing this 20-amino acid sequence (frameshift peptide 3877-3896) bound specifically to apoB86 but not to apoB100. Thus the compound heterozygotes had 2 mutant apoB alleles, one primarily responsible for apoB37 (107730.0001) and the other responsible for apoB86, both of which contained frameshift mutations in exon 26. Linton et al. (1992) further demonstrated that the 1-bp deletion in the apoB86 allele created a stretch of 8 consecutive adenines. Addition of a single adenine within the 8 consecutive adenines would be predicted to correct the altered reading frame, thereby resulting in the production of a full-length protein. They presented evidence that a significant percentage (about 11%) of the apoB cDNA clones from rat hepatoma cells transformed with an apoB construct containing the 1-bp deletion indeed had 9 consecutive adenines. It appeared that the addition of an extra adenine during transcription restored the correct reading frame and accounted for the formation of some apoB100 from the apoB86 allele. Other experiments were thought to exclude an alternative explanation, the activation of a cryptic splice site within exon 26 upstream from the deletion.

.0017 HYPERCHOLESTEROLEMIA DUE TO LIGAND-DEFECTIVE APOLIPOPROTEIN B

APOB, ARG3531CYS [dbSNP:rs12713559]

Suspecting that mutations in the APOB gene other than the arg3500-to-gln mutation (107730.0009) may cause familial hypercholesterolemia (144010), Pullinger et al. (1995) used single-strand conformation polymorphism analysis to screen genomic DNA from patients attending a lipid clinic and looked for mutations in the putative LDL receptor-binding domain of apoB100. They found a novel arg3531-to-cys mutation, caused by a C-to-T transition at nucleotide 10800, in a 46-year-old woman of Celtic and Native American ancestry with primary hypercholesterolemia and pronounced peripheral vascular disease. After screening 1,560 individuals, one unrelated 59-year-old man of Italian ancestry was found to have the same mutation. He had coronary heart disease, a triglyceride cholesterol of 310 mg/dl, and an LDL cholesterol of 212 mg/dl. A total of 8 individuals were found with the same defect in the families of these 2 patients. The age- and sex-adjusted TC and LDL-C were 240 and 169, respectively, for the 8 affected individuals, as compared with 185 and 124, respectively, for 8 unaffected family members. In a dual-labeled fibroblast binding assay, LDL from the 8 subjects with the mutation had an affinity for the LDL receptor that was 63% that of control LDL. LDL from 8 unaffected family members had an affinity of 91%. By way of comparison, LDL from 6 patients heterozygous for the arg3500-to-gln mutation had an affinity of 36%. Deduced haplotypes using 10 APOB gene markers showed the arg3531-to-cys alleles to be different in the 2 kindreds and indicated that the mutations arose independently. This was the second reported cause of familial ligand-defective apoB.

.0018 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, IVS7, A-G, -2

Hegele and Miskie (2002) described acanthocytosis in a 31-year-old woman with homozygous familial hypobetalipoproteinemia due to a splicing mutation in the APOB gene, IVS7AS-2A-G. Treatment with fat-soluble vitamins was associated with arrest of the usually progressive neurologic complications of this condition. However, acanthocytosis persisted. The diagnosis of hypobetalipoproteinemia was made at the age of 11 on the basis of acanthocytosis and the absence of apoB-containing lipoproteins. The consanguineous parents were heterozygotes.

.0019 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, 1-BP DEL, 4432T

Yue et al. (2002) described a 1-bp deletion, 4432delT, in exon 26 of the APOB gene, producing a frameshift and a premature stop codon and resulting in a truncated apoB-30.9. Although this truncation was only 10 amino acids shorter than the well-documented apoB31 (107730.0008), which is readily detectable in plasma, apoB-30.9 was undetectable. Most truncations shorter than apoB-30 are not detectable in plasma.

.0020 HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC

APOB, 4-BP DEL, NT36491

In a patient with normotriglyceridemic hypobetalipoproteinemia, obesity, and mental retardation, Homer et al. (2005) identified compound heterozygosity for 2 mutations in the APOB gene. One was a 4-bp deletion beginning at nucleotide 36491 in exon 26, predicted to result in a frameshift and incorporation of 5 new amino acids before encountering a premature termination codon at position 3053. This translated protein would be 66% of full-length apoB, which would allow for expression in the liver and for production of minute amounts of VLDL and LDL. Accordingly, the patient did not have failure to thrive or steatorrhea. The second mutation was a 29142T-A transversion in exon 23, resulting in a tyr1173-to-ter (Y1173X; 107730.0021) substitution. The translated Y1173X protein is predicted to be 25.8% of apoB100 and is not expressed in apoB-containing lipoproteins. Homer et al. (2005) suggested that the clinical features of ataxia, visual impairment, and probable neuropathy seen in the patient resulted from the inability to transport the active stereoisomer of vitamin E from the liver. These clinical features were similar to those seen in isolated vitamin E deficiency (VED; 277460). Homer et al. (2005) noted that the clinical features of this patient were similar to those of the patient reported by Malloy et al. (1981) (see 107730.0013).

Homer et al. (2005) suggested that the term 'normotriglyceridemic hypobetalipoproteinemia' is preferred to 'normotriglyceridemic abetalipoproteinemia' because abetalipoproteinemia (ABL; 200100) refers to the disorder caused by mutation in the MTP gene (157147).

.0021 HYPOBETALIPOPROTEINEMIA, NORMOTRIGLYCERIDEMIC

APOB, TYR1173TER [dbSNP:rs121918391]

See 107730.0020 and Homer et al. (2005).

.0022 HYPOBETALIPOPROTEINEMIA, FAMILIAL

APOB, 2-BP INS, 825GG

In a 27-year-old woman from a consanguineous French Canadian family, who was diagnosed with FHBL in the first months of life, Gangloff et al. (2011) identified a 2-bp insertion (825insGG) in exon 9 of the APOB gene, causing a frameshift predicted to result in a truncated protein that is approximately 7% of the normal APOB length. The proband and 2 younger brothers, aged 12 and 4 years, had undetectable apoB levels, extremely low levels of cholesterol in all lipoprotein fractions, low levels of lipophilic vitamins, and acanthocytosis. Vitamin E deficiency was present in all 3. The obligate-heterozygote parents had plasma levels of apoB-containing lipoproteins that were approximately 50% of normal, suggesting a codominant pattern of inheritance. The parents declined genetic testing for themselves and their younger children.

REFERENCES

1.	Aggerbeck, L. P., McMahon, J. P., Scanu, A. M. Hypobetalipoproteinemia: clinical and biochemical description of a new kindred with Friedreich's ataxia. Neurology 24: 1051-1063, 1974. [PubMed: 4472544, related citations] [Full Text: Pubget]

2.	Allison, A. C., Blumberg, B. S. An isoprecipitation reaction distinguishing human serum-protein types. Lancet 277: 634-637, 1961. Note: Originally Volume I. [PubMed: 13682582, related citations] [Full Text: Pubget]

3.	Allison, A. C., Blumberg, B. S. Serum lipoprotein allotypes in man. Prog. Med. Genet. 4: 176-201, 1965. [PubMed: 5319116, related citations] [Full Text: Pubget]

4.	Antonarakis, S. E. Personal Communication. Baltimore, Md. 6/1987.

5.	Araki, W., Hirose, S., Mimori, Y., Nakamura, S., Kimura, J., Ohno, K., Shimada, T. Familial hypobetalipoproteinaemia complicated by cerebellar ataxia and steatocystoma multiplex. J. Intern. Med. 229: 197-199, 1991. [PubMed: 1997645, related citations] [Full Text: Pubget]

6.	Barni, N., Talmud, P. J., Carlsson, P., Azoulay, M., Darnfors, C., Harding, D., Weil, D., Grzeschik, K. H., Bjursell, G., Junien, C., Williamson, R., Humphries, S. E. The isolation of genomic recombinants for the human apolipoprotein B gene and the mapping of three common DNA polymorphisms of the gene--a useful marker for human chromosome 2. Hum. Genet. 73: 313-319, 1986. [PubMed: 3017840, related citations] [Full Text: Pubget]

7.	Bednarska-Makaruk, M., Bisko, M., Pulawska, M. F., Hoffman-Zacharska, D., Rodo, M., Roszczynko, M., Solik-Tomassi, A., Broda, G., Polakowska, M., Pytlak, A., Wehr, H. Familial defective apolipoprotein B-100 in a group of hypercholesterolaemic patients in Poland: identification of a new mutation Thr3492Ile in the apolipoprotein B gene. Europ. J. Hum. Genet. 9: 836-842, 2001. [PubMed: 11781700, related citations] [Full Text: Nature Publishing Group, Pubget]

8.	Benlian, P., de Gennes, J. L., Dairou, F., Hermelin, B., Ginon, I., Villain, E., Lagarde, J. P., Federspiel, M. C., Bertrand, V., Bernard, C., Bereziat, G. Phenotypic expression in double heterozygotes for familial hypercholesterolemia and familial defective apolipoprotein B-100. Hum. Mutat. 7: 340-345, 1996. [PubMed: 8723684, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

9.	Benn, M., Nordestgaard, B. G., Jensen, J. S., Grande, P., Sillesen, H., Tybjaerg-Hansen, A. Polymorphism in APOB associated with increases low-density lipoprotein levels in both genders in the general population. J. Clin. Endocr. Metab. 90: 5797-5803, 2005. [PubMed: 16030169, related citations] [Full Text: HighWire Press, Pubget]

10.	Benn, M., Nordestgaard, B. G., Jensen, J. S., Tybjaerg-Hansen, A. Polymorphisms in apolipoprotein B and risk of ischemic stroke. J. Clin. Endocr. Metab. 92: 3611-3617, 2007. [PubMed: 17595251, related citations] [Full Text: HighWire Press, Pubget]

11.	Berg, K., Beckman, G., Beckman, L. A search for linkage between the Ag and (dimeric) superoxide dismutase (SOD-1) loci. Birth Defects Orig. Art. Ser. XI(3): 67-70, 1975. Note: Alternate: Cytogenet. Cell Genet. 14: 237-240, 1975.

12.	Berg, K., Hames, C., Dahlen, G., Frick, M. H., Krishan, I. Genetic variation in serum low density lipoproteins and lipid levels in man. Proc. Nat. Acad. Sci. 73: 937-940, 1976. [PubMed: 176662, related citations] [Full Text: Pubget]

13.	Berg, K., Powell, L. M., Wallis, S. C., Pease, R., Knott, T. J., Scott, J. Genetic linkage between the antigenic group (Ag) variation and the apolipoprotein B gene: assignment of the Ag locus. Proc. Nat. Acad. Sci. 83: 7367-7370, 1986. [PubMed: 2876424, related citations] [Full Text: HighWire Press, Pubget]

14.	Berger, G. M. B., Brown, G., Henderson, H. E., Bonnici, F. Apolipoprotein B detected in the plasma of a patient with homozygous hypobetalipoproteinaemia: implications for aetiology. J. Med. Genet. 20: 189-195, 1983. [PubMed: 6876109, related citations] [Full Text: HighWire Press, Pubget]

15.	Biemer, J. J., McCammon, R. E. The genetic relationship of abetalipoproteinemia and hypobetalipoproteinemia: a report of the occurrence of both diseases within the same family. J. Lab. Clin. Med. 85: 556-565, 1975. [PubMed: 164511, related citations] [Full Text: Pubget]

16.	Blumberg, B. S. Personal Communication. Philadelphia, Penn. 5/16/1978.

17.	Blumberg, B. S., Alter, H. J., Riddell, N. M. Inherited antigenic differences in human serum beta lipoproteins: a second antiserum. J. Clin. Invest. 42: 867-875, 1963. [PubMed: 13971876, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

18.	Blumberg, B. S., Alter, H. J., Riddell, N. M., Erlandson, M. Multiple antigenic specificities of serum lipoproteins detected with sera of transfused patients. Vox Sang. 9: 128-145, 1964. [PubMed: 14147429, related citations] [Full Text: Pubget]

19.	Boehnke, M. Allele frequency estimation from data on relatives. Am. J. Hum. Genet. 48: 22-25, 1991. [PubMed: 1985459, related citations] [Full Text: Pubget]

20.	Boerwinkle, E., Xiong, W., Fourest, E., Chan, L. Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: application to the apolipoprotein B 3-prime hypervariable region. Proc. Nat. Acad. Sci. 86: 212-216, 1989. [PubMed: 2911570, related citations] [Full Text: HighWire Press, Pubget]

21.	Boren, J., Ekstrom, U., Agren, B., Nilsson-Ehle, P., Innerarity, T. L. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J. Biol. Chem. 276: 9214-9218, 2001. [PubMed: 11115503, related citations] [Full Text: HighWire Press, Pubget]

22.	Boren, J., Lee, I., Zhu, W., Arnold, K., Taylor, S., Innerarity, T. L. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J. Clin. Invest. 101: 1084-1093, 1998. [PubMed: 9486979, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

23.	Breguet, G., Butler, R., Butler-Brunner, E., Sanchez-Mazas, A. A worldwide population study of the Ag-system haplotypes: a genetic polymorphism of human low-density lipoprotein. Am. J. Hum. Genet. 46: 502-517, 1990. [PubMed: 1689953, related citations] [Full Text: Pubget]

24.	Brown, B. J., Lewis, L. A., Mercer, R. D. Familial hypobetalipoproteinemia: report of a case with psychomotor retardation. Pediatrics 54: 111-113, 1974. [PubMed: 4365305, related citations] [Full Text: Pubget]

25.	Butler, R., Brunner, E. On the genetics of the low density lipoprotein factors Ag(c) and Ag(e). Hum. Hered. 19: 174-179, 1969. [PubMed: 5808059, related citations] [Full Text: Pubget]

26.	Butler, R., Brunner, E., Morganti, G., Vierucci, A., Scaloumbacas, N., Politis, E. A new factor in the Ag-system: Ag(g). Vox Sang. 18: 85-89, 1970. [PubMed: 4984720, related citations] [Full Text: Pubget]

27.	Callow, M. J., Verstuyft, J., Tangirala, R., Palinski, W., Rubin, E. M. Atherogenesis in transgenic mice with human apolipoprotein B and lipoprotein(a). J. Clin. Invest. 96: 1639-1646, 1995. [PubMed: 7657833, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

28.	Carlsson, P., Olofsson, S. O., Bondjers, G., Darnfors, C., Wiklund, O., Bjursell, G. Molecular cloning of human apolipoprotein B cDNA. Nucleic Acids Res. 13: 8813-8826, 1985. [PubMed: 3841204, related citations] [Full Text: HighWire Press, Pubget]

29.	Chan, L., VanTuinen, P., Ledbetter, D. H., Daiger, S. P., Gotto, A. M., Jr., Chen, S. H. The human apolipoprotein B-100 gene: a highly polymorphic gene that maps to the short arm of chromosome 2. Biochem. Biophys. Res. Commun. 133: 248-255, 1985. [PubMed: 4074366, related citations] [Full Text: Elsevier Science, Pubget]

30.	Chen, S.-H., Habib, G., Yang, C.-Y., Gu, Z.-W., Lee, B. R., Weng, S., Silberman, S. R., Cai, S.-J., Deslypere, J. P., Rosseneu, M., Gotto, A. M., Jr., Li, W.-H., Chan, L. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science 238: 363-366, 1987. [PubMed: 3659919, related citations] [Full Text: HighWire Press, Pubget]

31.	Chen, S.-H., Yang, C.-Y., Chen, P.-F., Setzer, D., Tanimura, M., Li, W. H., Gotto, A. M., Jr., Chan, L. The complete cDNA and amino acid sequence of human apolipoprotein B-100. J. Biol. Chem. 261: 12918-12921, 1986. [PubMed: 3759943, related citations] [Full Text: HighWire Press, Pubget]

32.	Cladaras, C., Hadzopoulou-Cladaras, M., Nolte, R. T., Atkinson, D., Zannis, V. I. The complete sequence and structural analysis of human apolipoprotein B-100: relationship between apoB-100 and apoB-48 forms. EMBO J. 5: 3495-3507, 1986. [PubMed: 3030729, related citations] [Full Text: Pubget]

33.	Collins, D. R., Knott, T. J., Pease, R. J., Powell, L. M., Wallis, S. C., Robertson, S., Pullinger, C. R., Milne, R. W., Marcel, Y. L., Humphries, S. E., Talmud, P. J., Lloyd, J. K., Miller, N. E., Muller, D., Scott, J. Truncated variants of apolipoprotein B cause hypobetalipoproteinaemia. Nucleic Acids Res. 16: 8361-8375, 1988. [PubMed: 2843815, related citations] [Full Text: HighWire Press, Pubget]

34.	Coresh, J., Beaty, T. H., Kwiterovich, P. O., Jr., Antonarakis, S. E. Pedigree and sib-pair linkage analysis suggest the apolipoprotein B gene is not the major gene influencing plasma apolipoprotein B levels. Am. J. Hum. Genet. 50: 1038-1045, 1992. [PubMed: 1570833, related citations] [Full Text: Pubget]

35.	Corsini, A., Fantappie, S., Granata, A., Bernini, F., Catapano, A. L., Fumagalli, R., Romano, L., Romano, C. Binding-defective low-density lipoprotein in family with hypercholesterolaemia.(Letter) Lancet 339: 623 only, 1989. Note: Originally Volume I. [PubMed: 2564152, related citations] [Full Text: Elsevier Science, Pubget]

36.	Cottrill, C., Glueck, C. J., Leuba, V., Millett, F., Puppione, D., Brown, W. V. Familial homozygous hypobetalipoproteinemia. Metabolism 23: 779-792, 1974. [PubMed: 4368720, related citations] [Full Text: Elsevier Science, Pubget]

37.	Deeb, S. S., Disteche, C., Motulsky, A. G., Lebo, R. V., Kan, Y. W. Chromosomal localization of the human apolipoprotein B gene and detection of homologous RNA in monkey intestine. Proc. Nat. Acad. Sci. 83: 419-422, 1986. [PubMed: 3455779, related citations] [Full Text: HighWire Press, Pubget]

38.	Demant, T., Houlston, R. S., Caslake, M. J., Series, J. J., Shepherd, J., Packard, C. J., Humphries, S. E. Catabolic rate of low density lipoprotein is influenced by variation in the apolipoprotein B gene. J. Clin. Invest. 82: 797-802, 1988. [PubMed: 2901432, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

39.	Di Leo, E., Magnolo, L., Bertolotti, M., Bourbon, M., Carmo Pereira, S., Pirisi, M., Calandra, S., Tarugi, P. Variable phenotypic expression of homozygous familial hypobetalipoproteinaemia due to novel APOB gene mutations. Clin. Genet. 74: 267-273, 2008. [PubMed: 18492086, related citations] [Full Text: Blackwell Publishing, Pubget]

40.	Di Leo, E., Magnolo, L., Lancellotti, S., Croce, L., Visintin, L., Tiribelli, C., Bertolini, S., Calandra, S., Tarugi, P. Abnormal apolipoprotein B pre-mRNA splicing in patients with familial hypobetalipoproteinemia. (Letter) J. Med. Genet. 44: 219-224, 2007. [PubMed: 17158591, related citations] [Full Text: HighWire Press, Pubget]

41.	Dunning, A. M., Renges, H.-H., Xu, C.-F., Peacock, R., Brasseur, R., Laxer, G., Tikkanen, M. J., Butler, R., Saha, N., Hamsten, A., Rosseneu, M., Talmud, P., Humphries, S. E. Two amino acid substitutions in apolipoprotein B are in complete allelic association with the antigen group (x/y) polymorphism: evidence for little recombination in the 3-prime end of the human gene. Am. J. Hum. Genet. 50: 208-221, 1992. [PubMed: 1370364, related citations] [Full Text: Pubget]

42.	Espinosa-Heidmann, D. G., Sall, J., Hernandez, E. P., Cousins, S. W. Basal laminar deposit formation in APO B100 transgenic mice: complex interactions between dietary fat, blue light, and vitamin E. Invest. Ophthal. Vis. Sci. 45: 260-266, 2004. [PubMed: 14691182, related citations] [Full Text: HighWire Press, Pubget]

43.	Farese, R. V., Jr., Veniant, M. M., Cham, C. M., Flynn, L. M., Pierotti, V., Loring, J. F., Traber, M., Ruland, S., Stokowski, R. S., Huszar, D., Young, S. G. Phenotypic analysis of mice expressing exclusively apolipoprotein B48 or apolipoprotein B100. Proc. Nat. Acad. Sci. 93: 6393-6398, 1996. [PubMed: 8692825, related citations] [Full Text: HighWire Press, Pubget]

44.	Feussner, G., Schuster, H. Screening for the apolipoprotein B-100 arginine3500-to-glutamine mutation in patients with type III hyperlipoproteinemia. Clin. Genet. 42: 302-305, 1992. [PubMed: 1493642, related citations] [Full Text: Pubget]

45.	Friedlander, Y., Dann, E. J., Leitersdorf, E. Absence of familial defective apolipoprotein B-100 in Israeli patients with dominantly inherited hypercholesterolemia and in offspring with parental history of myocardial infarction.(Letter) Hum. Genet. 91: 299-300, 1993. [PubMed: 8478017, related citations] [Full Text: Pubget]

46.	Frossard, P. M., Gonzalez, P. A., Protter, A. A., Coleman, R. T., Funke, H., Assmann, G. Pvu II RFLP in the 5-prime of the human apolipoprotein B gene. Nucleic Acids Res. 14: 4373, 1986. [PubMed: 3012469, related citations] [Full Text: HighWire Press, Pubget]

47.	Fujihara, M., Bartels, E., Nielsen, L. B., Handa, J. T. A human apoB100 transgenic mouse expresses human apoB100 in the RPE and develops features of early AMD. Exp. Eye Res. 88: 1115-1123, 2009. [PubMed: 19450445, related citations] [Full Text: Elsevier Science, Pubget]

48.	Gangloff, A., Bergeron, J., Couture, P., Martins, R., Hegele, R. A., Gagne, C. A novel mutation of apolipoprotein B in a French Canadian family with homozygous hypobetalipoproteinemia. J. Clin. Lipidol. 5: 414-417, 2011. [PubMed: 21981844, related citations] [Full Text: Elsevier Science, Pubget]

49.	Gavish, D., Brinton, E. A., Breslow, J. L. Heritable allele-specific differences in amounts of apoB and low-density lipoproteins in plasma. Science 244: 72-76, 1989. [PubMed: 2565046, related citations] [Full Text: HighWire Press, Pubget]

50.	Glickman, R. M., Rogers, M., Glickman, J. N. Apolipoprotein B synthesis by human liver and intestine in vitro. Proc. Nat. Acad. Sci. 83: 5296-5300, 1986. [PubMed: 3460091, related citations] [Full Text: HighWire Press, Pubget]

51.	Glueck, C. J., Tsang, R. C., Mellies, M. J., Fallat, R. W., Steiner, P. M. Neonatal familial hypobeta-lipoproteinemia. Metabolism 25: 611-614, 1976. [PubMed: 178979, related citations] [Full Text: Pubget]

52.	Hamalainen, T., Palotie, A., Aalto-Setala, K., Kontula, K., Tikkanen, M. J. Absence of familial defective apolipoprotein B-100 in Finnish patients with elevated serum cholesterol. Atherosclerosis 82: 177-183, 1990. [PubMed: 2375782, related citations] [Full Text: Pubget]

53.	Harano, Y., Kojima, H., Nakano, T., Harada, M., Kashiwagi, A., Nakajima, Y., Hidaka, T. H., Ohtsuki, T., Suzuki, T., Tamura, A., Fujii, T., Nishimura, T., Ohtaka, T., Shigeta, Y. Homozygous hypobetalipoproteinemia with spared chylomicron formation. Metabolism 38: 1-7, 1989. [PubMed: 2909827, related citations] [Full Text: Pubget]

54.	Hardman, D. A., Protter, A. A., Chen, G. C., Schilling, J. W., Sato, K. Y., Lau, K., Yamanaka, M., Mikita, T., Miller, J., Crisp, T., McEnroe, G., Scarborough, R. M., Kane, J. P. Structural comparisons of human apolipoproteins B-48 and B-100. Biochemistry 26: 5478-5486, 1987. [PubMed: 3676265, related citations] [Full Text: Pubget]

55.	Hardman, D. A., Pullinger, C. R., Hamilton, R. L., Kane, J. P., Malloy, M. J. Molecular and metabolic basis for the metabolic disorder normotriglyceridemic abetalipoproteinemia. J. Clin. Invest. 88: 1722-1729, 1991. [PubMed: 1939657, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

56.	Hegele, R. A., Huang, L.-S., Herbert, P. N., Blum, C. B., Buring, J. E., Hennekens, C. H., Breslow, J. L. Apolipoprotein B-gene polymorphisms associated with myocardial infarction. New Eng. J. Med. 315: 1509-1515, 1986. [PubMed: 3024002, related citations] [Full Text: Atypon, Pubget]

57.	Hegele, R. A., Miskie, B. A. Acanthocytosis in a patient with homozygous familial hypobetalipoproteinemia due to a novel APOB splice site mutation. Clin. Genet. 61: 101-103, 2002. [PubMed: 11940084, related citations] [Full Text: Blackwell Publishing, Pubget]

58.	Herbert, P. N., Hyams, J. S., Bernier, D. N., Berman, M. M., Saritelli, A. L., Lynch, K. M., Nichols, A. V., Forte, T. M. Apolipoprotein B-100 deficiency: intestinal steatosis despite apolipoprotein B-48 synthesis. J. Clin. Invest. 76: 403-412, 1985. [PubMed: 4031057, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

59.	Higuchi, K., Hospattankar, A. V., Law, S. W., Meglin, N., Cortright, J., Brewer, H. B., Jr. Human apolipoprotein B (apoB) mRNA: identification of two distinct apoB mRNAs, an mRNA with the apoB-100 sequence and an apoB mRNA containing a premature in-frame translational stop codon, in both liver and intestine. Proc. Nat. Acad. Sci. 85: 1772-1776, 1988. [PubMed: 2450346, related citations] [Full Text: HighWire Press, Pubget]

60.	Homanics, G. E., Smith, T. J., Zhang, S. H., Lee, D., Young, S. G., Maeda, N. Targeted modification of the apolipoprotein B gene results in hypobetalipoproteinemia and developmental abnormalities in mice. Proc. Nat. Acad. Sci. 90: 2389-2393, 1993. [PubMed: 8460149, related citations] [Full Text: HighWire Press, Pubget]

61.	Homer, V. M., George, P. M., du Toit, S., Davidson, J. S., Wilson, C. J. Mental retardation and ataxia due to normotriglyceridemic hypobetalipoproteinemia. Ann. Neurol. 58: 160-163, 2005. [PubMed: 15984016, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

62.	Horvath, A., Savov, A., Kirov, S., Karshelova, E., Paskaleva, I., Goudev, A., Ganev, V. High frequency of the ApoB-100 R3500Q mutation in Bulgarian hypercholesterolaemic subjects. J. Med. Genet. 38: 536-540, 2001. [PubMed: 11494965, related citations] [Full Text: HighWire Press, Pubget]

63.	Hospattankar, A. V., Fairwell, T., Meng, M., Ronan, R., Brewer, H. B., Jr. Identification of sequence homology between human plasma apolipoprotein B-100 and apolipoprotein B-48. J. Biol. Chem. 261: 9102-9104, 1986. [PubMed: 3522585, related citations] [Full Text: HighWire Press, Pubget]

64.	Huang, L.-S., Miller, D. A., Bruns, G. A. P., Breslow, J. L. Mapping of the human APOB gene to chromosome 2p and demonstration of a two-allele restriction fragment length polymorphism. Proc. Nat. Acad. Sci. 83: 644-648, 1986. [PubMed: 3003743, related citations] [Full Text: HighWire Press, Pubget]

65.	Huang, L.-S., Ripps, M. E., Korman, S. H., Deckelbaum, R. J., Breslow, J. L. Hypobetalipoproteinemia due to an apolipoprotein B gene exon 21 deletion derived by Alu-Alu recombination. J. Biol. Chem. 264: 11394-11400, 1989. [PubMed: 2567736, related citations] [Full Text: HighWire Press, Pubget]

66.	Huang, L.-S., Voyiaziakis, E., Chen, H. L., Rubin, E. M., Gordon, J. W. A novel functional role for apolipoprotein B in male infertility in heterozygous apolipoprotein B knockout mice. Proc. Nat. Acad. Sci. 93: 10903-10907, 1996. [PubMed: 8855280, related citations] [Full Text: HighWire Press, Pubget]

67.	Huang, L.-S., Voyiaziakis, E., Markenson, D. F., Sokol, K. A., Hayek, T., Breslow, J. L. apo B gene knockout in mice results in embryonic lethality in homozygotes and neural tube defects, male infertility, and reduced HDL cholesterol ester and apo A-1 transport rates in heterozygotes. J. Clin. Invest. 96: 2152-2161, 1995. [PubMed: 7593600, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

68.	Illingworth, D. R., Connor, W. E., Buist, N. R. M., Jhaveri, B. M., Lin, S. S., McMurry, M. P. Sterol balance in abetalipoproteinemia: studies in a patient with homozygous familial hypobetalipoproteinemia. Metabolism 28: 1152-1160, 1979. [PubMed: 491973, related citations] [Full Text: Elsevier Science, Pubget]

69.	Illingworth, D. R., Vakar, F., Mahley, R. W., Weisgraber, K. H. Hypocholesterolaemic effects of lovastatin in familial defective apolipoprotein B-100. Lancet 339: 598-600, 1992. [PubMed: 1347103, related citations] [Full Text: Elsevier Science, Pubget]

70.	Innerarity, T. L., Weisgraber, K. H., Arnold, K. S., Mahley, R. W., Krauss, R. M., Vega, G. L., Grundy, S. M. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc. Nat. Acad. Sci. 84: 6919-6923, 1987. [PubMed: 3477815, related citations] [Full Text: HighWire Press, Pubget]

71.	Innerarity, T. L., Young, S. G., Poksay, K. S., Mahley, R. W., Smith, R. S., Milne, R. W., Marcel, Y. L., Weisgraber, K. H. Structural relationship of human apolipoprotein B48 to apolipoprotein B100. J. Clin. Invest. 80: 1794-1798, 1987. [PubMed: 3680528, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

72.	Jackson, L., Falk, C. T., Allen, F. H., Jr., Barr, M. A possible gene assignment to chromosome 21. Cytogenet. Cell Genet. 13: 100-102, 1974. [PubMed: 4363864, related citations] [Full Text: Pubget]

73.	Kahn, J. A., Glueck, C. J. Familial hypobetalipoproteinemia: absence of atherosclerosis in a postmortem study. JAMA 240: 47-48, 1978. [PubMed: 207903, related citations] [Full Text: Pubget]

74.	Kairamkonda, V., Dalzell, M. Unusual presentation of three siblings with familial heterozygous hypobetalipoproteinaemia. Europ. J. Pediat. 162: 129-131, 2003. [PubMed: 12655413, related citations] [Full Text: Springer, Pubget]

75.	Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M. Polymorphisms associated with cholesterol and risk of cardiovascular events. New Eng. J. Med. 358: 1240-1249, 2008. [PubMed: 18354102, related citations] [Full Text: Atypon, Pubget]

76.	Keidar, S., Etzioni, A., Brook, J. G., Gershoni-Baruch, R., Aviram, M. Compound heterozygosity for abetalipoproteinaemia and familial hypobetalipoproteinaemia. J. Med. Genet. 27: 133-134, 1990. [PubMed: 2319582, related citations] [Full Text: HighWire Press, Pubget]

77.	Knott, T. J., Pease, R. J., Powell, L. M., Wallis, S. C., Rall, S. C., Jr., Innerarity, T. L., Blackhart, B., Taylor, W. H., Marcel, Y., Milne, R., Johnson, D., Fuller, M., Lusis, A. J., McCarthy, B. J., Mahley, R. W., Levy-Wilson, B., Scott, J. Complete protein sequence and identification of structural domains of human apolipoprotein B. Nature 323: 734-738, 1986. [PubMed: 3773997, related citations] [Full Text: Nature Publishing Group, Pubget]

78.	Knott, T. J., Rall, S. C., Jr., Innerarity, T. L., Jacobson, S. F., Urdea, M. S., Levy-Wilson, B., Powell, L. M., Pease, R. J., Eddy, R., Nakai, H., Byers, M., Priestley, L. M., Robertson, E., Rall, L. B., Betsholtz, C., Shows, T. B., Mahley, R. W., Scott, J. Human apolipoprotein B: structure of carboxyl-terminal domains, sites of gene expression, and chromosomal localization. Science 230: 37-43, 1985. [PubMed: 2994225, related citations] [Full Text: HighWire Press, Pubget]

79.	Knott, T. J., Wallis, S. C., Powell, L. M., Pease, R. J., Lusis, A. J., Blackhart, B., McCarthy, B. J., Mahley, R. W., Levy-Wilson, B., Scott, J. Complete cDNA and derived protein sequence of human apolipoprotein B-100. Nucleic Acids Res. 14: 7501-7503, 1986. [PubMed: 3763409, related citations] [Full Text: HighWire Press, Pubget]

80.	Krul, E. S., Kinoshita, M., Talmud, P., Humphries, S. E., Turner, S., Goldberg, A. C., Cook, K., Boerwinkle, E., Schonfeld, G. Two distinct truncated apolipoprotein B species in a kindred with hypobetalipoproteinemia. Arteriosclerosis 9: 856-868, 1989. [PubMed: 2574033, related citations] [Full Text: HighWire Press, Pubget]

81.	Lau, P. P., Zhu, H.-J., Baldini, A., Charnsangavej, C., Chan, L. Dimeric structure of a human apolipoprotein B mRNA editing protein and cloning and chromosomal localization of its gene. Proc. Nat. Acad. Sci. 91: 8522-8526, 1994. [PubMed: 8078915, related citations] [Full Text: HighWire Press, Pubget]

82.	Law, A., Wallis, S. C., Powell, L. M., Pease, R. J., Brunt, H., Priestley, L. M., Knott, T. J., Scott, J., Altman, D. G., Miller, G. J., Rajput, J., Miller, N. E. Common DNA polymorphism within coding sequence of apolipoprotein B gene associated with altered lipid levels. Lancet 327: 1301-1303, 1986. Note: Originally Volume I. [PubMed: 2872432, related citations] [Full Text: Pubget]

83.	Law, S. W., Grant, S. M., Higuchi, K., Hospattankar, A., Lackner, K., Lee, N., Brewer, H. B., Jr. Human liver apolipoprotein B-100 cDNA: complete nucleic acid and derived amino acid sequence. Proc. Nat. Acad. Sci. 83: 8142-8146, 1986. [PubMed: 3464946, related citations] [Full Text: HighWire Press, Pubget]

84.	Law, S. W., Lackner, K. J., Hospattankar, A. V., Anchors, J. M., Sakaguchi, A. Y., Naylor, S. L., Brewer, H. B., Jr. Human apolipoprotein B-100: cloning, analysis of liver mRNA, and assignment of the gene to chromosome 2. Proc. Nat. Acad. Sci. 82: 8340-8344, 1985. [PubMed: 3001697, related citations] [Full Text: HighWire Press, Pubget]

85.	Leppert, M., Breslow, J. L., Wu, L., Hasstedt, S., O'Connell, P., Lathrop, M., Williams, R. R., White, R., Lalouel, J.-M. Inference of a molecular defect of apolipoprotein B in hypobetalipoproteinemia by linkage analysis in a large kindred. J. Clin. Invest. 82: 847-851, 1988. [PubMed: 2901434, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

86.	Linton, M. F., Farese, R. V., Jr., Young, S. G. Familial hypobetalipoproteinemia. J. Lipid Res. 34: 521-541, 1993. [PubMed: 8496659, related citations] [Full Text: HighWire Press, Pubget]

87.	Linton, M. F., Pierotti, V., Young, S. G. Reading-frame restoration with an apolipoprotein B gene frameshift mutation. Proc. Nat. Acad. Sci. 89: 11431-11435, 1992. [PubMed: 1454832, related citations] [Full Text: HighWire Press, Pubget]

88.	Loux, N., Saint-Jore, B., Collod, G., Benlian, P., Cambou, J. P., Denat, M., Junien, C., Boileau, C. Identification of the haplotype associated with the APOB-3500 mutation in a French hypercholesterolemic subject: further support for a unique European ancestral mutation. Hum. Mutat. 2: 145-147, 1993. [PubMed: 8318993, related citations] [Full Text: Pubget]

89.	Ludwig, E. H., Friedl, W., McCarthy, B. J. High-resolution analysis of a hypervariable region in the human apolipoprotein B gene. Am. J. Hum. Genet. 45: 458-464, 1989. [PubMed: 2773938, related citations] [Full Text: Pubget]

90.	Ludwig, E. H., McCarthy, B. J. Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B100. Am. J. Hum. Genet. 47: 712-720, 1990. [PubMed: 1977310, related citations] [Full Text: Pubget]

91.	Lusis, A. J., West, R., Mehrabian, M., Reuben, M. A., LeBoeuf, R. C., Kaptein, J. S., Johnson, D. F., Schumaker, V. N., Yuhasz, M. P., Schotz, M. C., Elovson, J. Cloning and expression of apolipoprotein B, the major protein of low and very low density lipoproteins. Proc. Nat. Acad. Sci. 82: 4597-4601, 1985. [PubMed: 3860811, related citations] [Full Text: HighWire Press, Pubget]

92.	Malloy, M. J., Kane, J. P., Hardman, D. A., Hamilton, R. L., Dalal, K. B. Normotriglyceridemic abetalipoproteinemia: absence of the B-100 apolipoprotein. J. Clin. Invest. 67: 1441-1450, 1981. [PubMed: 7229035, related citations] [Full Text: Pubget]

93.	Mars, H., Lewis, L. A., Robertson, A. L., Jr., Butkus, A., Williams, G. H., Jr. Familial hypobetalipoproteinemia: a genetic disorder of lipid metabolism with nervous system involvement. Am. J. Med. 46: 886-900, 1969. [PubMed: 4978919, related citations] [Full Text: Pubget]

94.	Marz, W., Baumstark, M. W., Scharnagl, H., Ruzicka, V., Buxbaum, S., Herwig, J., Pohl, T., Russ, A., Schaaf, L., Berg, A., Bohles, H.-J., Usadel, K. H., Gro, W. Accumulation of 'small dense' low density lipoproteins (LDL) in a homozygous patient with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor. J. Clin. Invest. 92: 2922-2933, 1993. [PubMed: 8254047, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

95.	Marz, W., Ruzicka, C., Pohl, T., Usadel, K. H., Gross, W. Familial defective apolipoprotein B-100: mild hypercholesterolaemia without atherosclerosis in a homozygous patient.(Letter) Lancet 340: 1362, 1992. [PubMed: 1360085, related citations] [Full Text: Elsevier Science, Pubget]

96.	McCormick, S. P. A., Fellowes, A. P., Walmsley, T. A., George, P. M. Apolipoprotein B-32: a new truncated mutant of human apolipoprotein B capable of forming particles in the low density lipoprotein range. Biochim. Biophys. Acta 1138: 290-296, 1992. [PubMed: 1562615, related citations] [Full Text: Pubget]

97.	McKusick, V. A. Personal Communication. Baltimore, Md. 1983.

98.	Mehrabian, M., Sparkes, R. S., Mohandas, T., Klisak, I. J., Schumaker, V. N., Heinzmann, C., Zollman, S., Ma, Y., Lusis, A. J. Human apolipoprotein B: chromosomal mapping and DNA polymorphisms of hepatic and intestinal species. Somat. Cell Molec. Genet. 12: 245-254, 1986. [PubMed: 3012797, related citations] [Full Text: Pubget]

99.	Morganti, G., Beolchini, P. B., Butler, R., Butler-Brunner, E., Vierucci, A. Contribution to the genetics of serum beta-lipoproteins in man. VIII. Linkage of the Ag(h-i)locus with the Ag(x-y), Ag(a1-d), Ag(c-g), and Ag(t-z) loci. Humangenetik 30: 341-342, 1975. [PubMed: 176106, related citations] [Full Text: Pubget]

100.	Morganti, G., Beolchini, P. E., Butler, R., Brunner, E., Vierucci, A. Contribution to the genetics of serum beta-lipoproteins in man. IV. Evidence for the existence of the Ag(A1-D) and Ag(C-G) loci, closely linked to the Ag(X-Y) locus. Humangenetik 10: 244-253, 1970. [PubMed: 5475509, related citations] [Full Text: Pubget]

101.	Myant, N. B., Forbes, S. A., Day, I. N. M., Gallaghers, J. Estimation of the age of the ancestral arginine3500-to-glutamine mutation in human apoB-100. Genomics 45: 78-87, 1997. [PubMed: 9339363, related citations] [Full Text: Elsevier Science, Pubget]

102.	Naganawa, S., Kodama, T., Aburatani, H., Matsumoto, A., Itakura, H., Takashima, Y., Kawamura, M., Muto, Y. Genetic analysis of a Japanese family with normotriglyceridemic abetalipoproteinemia indicates a lack of linkage to the apolipoprotein B gene. Biochem. Biophys. Res. Commun. 182: 99-104, 1992. [PubMed: 1731805, related citations] [Full Text: Elsevier Science, Pubget]

103.	Parhofer, K. G., Barrett, P. H. R., Bier, D. M., Schonfeld, G. Lipoproteins containing the truncated apolipoprotein, apoB-89, are cleared from human plasma more rapidly than apoB-100-containing lipoproteins in vivo. J. Clin. Invest. 89: 1931-1937, 1992. [PubMed: 1602000, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

104.	Parker, C. R., Jr., Illingworth, D. R., Bissonnette, J., Carr, B. R. Endocrine changes during pregnancy in a patient with homozygous familial hypobetalipoproteinemia. New Eng. J. Med. 314: 557-560, 1986. [PubMed: 3945294, related citations] [Full Text: Atypon, Pubget]

105.	Protter, A. A., Hardman, D. A., Sato, K. Y., Schilling, J. W., Yamanaka, M., Hort, Y. J., Hjerrild, K. A., Chen, G. C., Kane, J. P. Analysis of cDNA clones encoding the entire B-26 region of human apolipoprotein B. Proc. Nat. Acad. Sci. 83: 5678-5682, 1986. [PubMed: 3461454, related citations] [Full Text: HighWire Press, Pubget]

106.	Protter, A. A., Hardman, D. A., Schilling, J. W., Miller, J., Appleby, V., Chen, G. C., Kirsher, S. W., McEnroe, G., Kane, J. P. Isolation of a cDNA clone encoding the amino-terminal region of human apolipoprotein B. Proc. Nat. Acad. Sci. 83: 1467-1471, 1986. [PubMed: 3513177, related citations] [Full Text: HighWire Press, Pubget]

107.	Pulai, J. I., Neuman, R. J., Groenewegen, A. W., Wu, J., Schonfeld, G. Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the apoB gene in Caucasian families. Am. J. Med. Genet. 76: 79-86, 1998. [PubMed: 9508071, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

108.	Pullinger, C. R., Hennessy, L. K., Chatterton, J. E., Liu, W., Love, J. A., Mendel, C. M., Frost, P. H., Malloy, M. J., Schumaker, V. N., Kane, J. P. Familial ligand-defective apolipoprotein B: identification of a new mutation that decreases LDL receptor binding affinity. J. Clin. Invest. 95: 1225-1234, 1995. [PubMed: 7883971, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

109.	Rajput-Williams, J., Knott, T. J., Wallis, S. C., Sweetnam, P., Yarnell, J., Cox, N., Bell, G. I., Miller, N. E., Scott, J. Variation of apolipoprotein-B gene is associated with obesity, high blood cholesterol levels, and increased risk of coronary heart disease. Lancet 332: 1442-1446, 1988. Note: Originally Volume II. [PubMed: 2904569, related citations] [Full Text: Elsevier Science, Pubget]

110.	Rapacz, J., Hasler-Rapacz, J., Taylor, K. M., Checovich, W. J., Attie, A. D. Lipoprotein mutations in pigs are associated with elevated plasma cholesterol and atherosclerosis. Science 234: 1573-1577, 1986. [PubMed: 3787263, related citations] [Full Text: HighWire Press, Pubget]

111.	Rauh, G., Keller, C., Schuster, H., Wolfram, G., Zollner, N. Familial defective apolipoprotein B-100: a common cause of primary hypercholesterolemia. Clin. Invest. 70: 77-84, 1992. [PubMed: 1600334, related citations] [Full Text: Pubget]

112.	Ross, R. S., Gregg, R. E., Law, S. W., Monge, J. C., Grant, S. M., Higuchi, K., Triche, T. J., Jefferson, J., Brewer, H. B., Jr. Homozygous hypobetalipoproteinemia: a disease distinct from abetalipoproteinemia at the molecular level. J. Clin. Invest. 81: 590-595, 1988. [PubMed: 2828430, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

113.	Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.

114.	Rubinsztein, D. C., Raal, F. J., Seftel, H. C., Pilcher, G., Coetzee, G. A., van der Westhuyzen, D. R. Characterization of six patients who are double heterozygotes for familial hypercholesterolemia and familial defective apo B-100. Arterioscler. Thromb. 13: 1076-1081, 1993. [PubMed: 8318509, related citations] [Full Text: HighWire Press, Pubget]

115.	Saint-Jore, B., Varret, M., Dachet, C., Rabes, J.-P., Devillers, M., Erlich, D., Blanchard, P., Krempf, M., Mathe, D., Chanu, B., Jacotot, B., Farnier, M., Bonaiti-Pellie, C., Junien, C., Boileau, C. Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects. Europ. J. Hum. Genet. 8: 621-630, 2000. [PubMed: 10952765, related citations] [Full Text: Nature Publishing Group, Pubget]

116.	Schaefer, J. R., Scharnagl, H., Baumstark, M. W., Schweer, H., Zech, L. A., Seyberth, H., Winkler, K., Steinmetz, A., Marz, W. Homozygous familial defective apolipoprotein B-100: enhanced removal of apolipoprotein E-containing VLDLs and decreased production of LDLs. Arteriosclerosis Thromb. Vasc. Biol. 17: 348-353, 1997.

117.	Schonfeld, G. Personal Communication. St. Louis, Mo. 3/24/1998.

118.	Shoulders, C. C., Myant, N. B., Sidoli, A., Rodriguez, J. C., Cortese, C., Baralle, F. E., Cortese, R. Molecular cloning of human LDL apolipoprotein B cDNA: evidence for more than one gene per haploid genome. Atherosclerosis 58: 277-289, 1985. [PubMed: 3841481, related citations] [Full Text: Pubget]

119.	Singh, M. K., Pandey, U. B., Ghoshal, U. C., Srivenu, I., Kapoor, V. K., Choudhuri, G., Mittal, B. Apolipoprotein B-100 XbaI gene polymorphism in gallbladder cancer. Hum. Genet. 114: 280-283, 2004. [PubMed: 14618390, related citations] [Full Text: Springer, Pubget]

120.	Skalen, K., Gustafsson, M., Rydberg, E. K., Hulten, L. M., Wiklund, O., Innerarity, T. L., Boren, J. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417: 750-754, 2002. [PubMed: 12066187, related citations] [Full Text: Nature Publishing Group, Pubget]

121.	Soria, L. F., Ludwig, E. H., Clarke, H. R. G., Vega, G. L., Grundy, S. M., McCarthy, B. J. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc. Nat. Acad. Sci. 86: 587-591, 1989. [PubMed: 2563166, related citations] [Full Text: HighWire Press, Pubget]

122.	Soutschek, J., Akinc, A., Bramlage, B., Charisse, K., Constien, R., Donoghue, M., Elbashir, S., Geick, A., Hadwiger, P., Harborth, J., John, M., Kesavan, V., and 13 others. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432: 173-178, 2004. [PubMed: 15538359, related citations] [Full Text: Nature Publishing Group, Pubget]

123.	Steinberg, D., Grundy, S. M., Mok, H. Y. I., Turner, J. D., Weinstein, D. B., Brown, W. V., Albers, J. J. Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypoalphalipoproteinemia and fasting chylomicronemia. J. Clin. Invest. 64: 292-301, 1979. [PubMed: 221546, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

124.	Takashima, Y., Kodama, T., Iida, H., Kawamura, M., Aburatani, H., Itakura, H., Akanuma, Y., Takaku, F., Kawade, M. Normotriglyceridemic abetalipoproteinemia in infancy: an isolated apolipoprotein B-100 deficiency. Pediatrics 75: 541-546, 1985. [PubMed: 3975124, related citations] [Full Text: Pubget]

125.	Talmud, P., King-Underwood, L., Krul, E., Schonfeld, G., Humphries, S. The molecular basis of truncated forms of apolipoprotein B in a kindred with compound heterozygous hypobetalipoproteinemia. J. Lipid Res. 30: 1773-1779, 1989. [PubMed: 2614276, related citations] [Full Text: HighWire Press, Pubget]

126.	Talmud, P. J., Converse, C., Krul, E., Huq, L., McIlwaine, G. G., Series, J. J., Boyd, P., Schonfeld, G., Dunning, A., Humphries, S. A novel truncated apolipoprotein B (apo B55) in a patient with familial hypobetalipoproteinemia and atypical retinitis pigmentosa. Clin. Genet. 42: 62-70, 1992. [PubMed: 1424233, related citations] [Full Text: Pubget]

127.	Talmud, P. J., Lloyd, J. K., Muller, D. P. R., Collins, D. R., Scott, J., Humphries, S. Genetic evidence from two families that the apolipoprotein B gene is not involved in abetalipoproteinemia. J. Clin. Invest. 82: 1803-1806, 1988. [PubMed: 2903181, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

128.	Tamir, I., Levtow, O., Lotan, D., Legum, C., Heldenberg, D., Werbin, B. Further observations on familial hypobetalipoproteinemia. Clin. Genet. 9: 149-155, 1976. [PubMed: 174851, related citations] [Full Text: Pubget]

129.	Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., Johansen, C. T., Fouchier, S. W., and 197 others. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466: 707-713, 2010. [PubMed: 20686565, related citations] [Full Text: Nature Publishing Group, Pubget]

130.	Tybjaerg-Hansen, A., Humphries, S. E. Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease. Atherosclerosis 96: 91-107, 1992. [PubMed: 1466657, related citations] [Full Text: Pubget]

131.	Tybjaerg-Hansen, A., Steffensen, R., Meinertz, H., Schnohr, P., Nordestgaard, B. G. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. New Eng. J. Med. 338: 1577-1584, 1998. [PubMed: 9603795, related citations] [Full Text: Atypon, Pubget]

132.	Vega, G. L., Grundy, S. M. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J. Clin. Invest. 78: 1410-1414, 1986. [PubMed: 3771801, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

133.	Visvikis, S., Chan, L., Siest, G., Drouin, P., Boerwinkle, E. An insertion deletion polymorphism in the signal peptide of the human apolipoprotein B gene. Hum. Genet. 84: 373-375, 1990. [PubMed: 2307462, related citations] [Full Text: Pubget]

134.	Weisgraber, K. H., Innerarity, T. L., Newhouse, Y. M., Young, S. G., Arnold, K. S., Krauss, R. M., Vega, G. L., Grundy, S. M., Mahley, R. W. Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc. Nat. Acad. Sci. 85: 9758-9762, 1988. [PubMed: 3200853, related citations] [Full Text: HighWire Press, Pubget]

135.	Welty, F. K., Hubl, S. T., Pierotti, V. R., Young, S. G. A truncated species of apolipoprotein B (B67) in a kindred with familial hypobetalipoproteinemia. J. Clin. Invest. 87: 1748-1754, 1991. [PubMed: 2022744, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

136.	Xu, C., Nanjee, N., Tikkanen, M. J., Huttunen, J. K., Pietinen, P., Butler, R., Angelico, F., Del Ben, M., Mazzarella, B., Antonio, R., Miller, N. G., Humphries, S., Talmud, P. J. Apolipoprotein B amino acid 3611 substitution from arginine to glutamine creates the Ag (h/i) epitope: the polymorphism is not associated with differences in serum cholesterol and apolipoprotein B levels. Hum. Genet. 82: 322-326, 1989. [PubMed: 2472350, related citations] [Full Text: Pubget]

137.	Yang, C.-Y., Chen, S.-H., Gianturco, S. H., Bradley, W. A., Sparrow, J. T., Tanimura, M., Li, W.-H., Sparrow, D. A., DeLoof, H., Rosseneu, M., Lee, F.-S., Gu, Z.-W., Gotto, A. M., Jr., Chan, L. Sequence, structure, receptor-binding domains and internal repeats of human apolipoprotein B-100. Nature 323: 738-742, 1986. [PubMed: 3095664, related citations] [Full Text: Nature Publishing Group, Pubget]

138.	Young, S. G., Bertics, S. J., Curtiss, L. K., Casal, D. C., Witztum, J. L. Monoclonal antibody MB19 detects genetic polymorphism in human apolipoprotein B. Proc. Nat. Acad. Sci. 83: 1101-1105, 1986. [PubMed: 2419898, related citations] [Full Text: HighWire Press, Pubget]

139.	Young, S. G., Bertics, S. J., Curtiss, L. K., Dubois, B. W., Witztum, J. L. Genetic analysis of a kindred with familial hypobetalipoproteinemia: evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100. J. Clin. Invest. 79: 1842-1851, 1987. [PubMed: 3473077, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

140.	Young, S. G., Bertics, S. J., Curtiss, L. K., Witztum, J. L. Characterization of an abnormal species of apolipoprotein B, apolipoprotein B-37, associated with familial hypobetalipoproteinemia. J. Clin. Invest. 79: 1831-1841, 1987. [PubMed: 3584472, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

141.	Young, S. G., Bertics, S. J., Scott, T. M., Dubois, B. W., Curtiss, L. K., Witztum, J. L. Parallel expression of the MB19 genetic polymorphism in apoprotein B-100 and apoprotein B-48: evidence that both apoproteins are products of the same gene. J. Biol. Chem. 261: 2995-2998, 1986. [PubMed: 3949756, related citations] [Full Text: HighWire Press, Pubget]

142.	Young, S. G., Hubl, S. T., Chappell, D. A., Smith, R. S., Claiborne, F., Snyder, S. M., Terdiman, J. F. Familial hypobetalipoproteinemia associated with a mutant species of apolipoprotein B (B-46). New Eng. J. Med. 320: 1604-1610, 1989. [PubMed: 2725600, related citations] [Full Text: Atypon, Pubget]

143.	Young, S. G., Hubl, S. T., Smith, R. S., Snyder, S. M., Terdiman, J. F. Familial hypobetalipoproteinemia caused by a mutation in the apolipoprotein B gene that results in a truncated species of apolipoprotein B (B-31): a unique mutation that helps to define the portion of the apolipoprotein B molecule required for the formation of buoyant, triglyceride-rich lipoproteins. J. Clin. Invest. 85: 933-942, 1990. [PubMed: 2312735, related citations] [Full Text: Journal of Clinical Investigation, Pubget]

144.	Young, S. G., Northey, S. T., McCarthy, B. J. Low plasma cholesterol levels caused by a short deletion in the apolipoprotein B gene. Science 241: 591-593, 1988. [PubMed: 3399894, related citations] [Full Text: HighWire Press, Pubget]

145.	Yue, P., Yuan, B., Gerhard, D. S., Neuman, R. J., Isley, W. L., Harris, W. S., Schonfeld, G. Novel mutations of APOB cause ApoB truncations undetectable in plasma and familial hypobetalipoproteinemia. Hum. Mutat. 20: 110-116, 2002. [PubMed: 12124991, related citations] [Full Text: John Wiley & Sons, Inc., Pubget]

Contributors:	Marla J. F. O'Neill - updated : 10/24/2011
	Marla J. F. O'Neill - updated : 4/21/2011 Ada Hamosh - updated : 9/27/2010 Marla J. F. O'Neill - updated : 5/7/2009 Ada Hamosh - updated : 4/1/2008 John A. Phillips, III - updated : 3/21/2008 Ada Hamosh - updated : 6/27/2007 Marla J. F. O'Neill - updated : 6/7/2007 John A. Phillips, III - updated : 5/11/2007 Cassandra L. Kniffin - updated : 1/5/2006 Jane Kelly - updated : 6/14/2004 Natalie E. Krasikov - updated : 3/2/2004 Victor A. McKusick - updated : 2/9/2004 Victor A. McKusick - updated : 8/20/2002 Michael B. Petersen - updated : 8/5/2002 Michael J. Wright - updated : 7/29/2002 Ada Hamosh - updated : 7/10/2002 Victor A. McKusick - updated : 5/10/2002 Victor A. McKusick - updated : 4/12/2001 Victor A. McKusick - updated : 3/15/2001 Victor A. McKusick - updated : 7/30/1998 Victor A. McKusick - updated : 5/18/1998 Victor A. McKusick - updated : 4/13/1998 Victor A. McKusick - updated : 10/13/1997 Victor A. McKusick - updated : 5/16/1997
Creation Date:	Victor A. McKusick : 6/16/1986
Edit History:	carol : 10/24/2011
	carol : 10/24/2011 terry : 10/24/2011 terry : 10/13/2011 joanna : 10/5/2011 terry : 6/17/2011 wwang : 4/21/2011 alopez : 9/27/2010 alopez : 9/27/2010 terry : 6/3/2009 wwang : 5/11/2009 terry : 5/7/2009 terry : 2/3/2009 terry : 1/7/2009 wwang : 5/21/2008 terry : 5/19/2008 carol : 4/14/2008 carol : 4/2/2008 carol : 4/1/2008 carol : 3/21/2008 alopez : 7/5/2007 terry : 6/27/2007 wwang : 6/13/2007 terry : 6/7/2007 alopez : 5/11/2007 wwang : 9/21/2006 wwang : 1/12/2006 ckniffin : 1/5/2006 terry : 5/17/2005 terry : 4/18/2005 alopez : 6/14/2004 carol : 3/17/2004 carol : 3/2/2004 cwells : 2/18/2004 terry : 2/9/2004 alopez : 5/16/2003 mgross : 10/25/2002 tkritzer : 8/26/2002 tkritzer : 8/23/2002 terry : 8/20/2002 tkritzer : 8/7/2002 tkritzer : 8/7/2002 tkritzer : 8/5/2002 alopez : 7/31/2002 terry : 7/29/2002 alopez : 7/11/2002 terry : 7/10/2002 ckniffin : 6/5/2002 alopez : 5/28/2002 terry : 5/10/2002 mcapotos : 4/24/2001 mcapotos : 4/18/2001 terry : 4/12/2001 carol : 3/29/2001 mcapotos : 3/26/2001 mcapotos : 3/22/2001 terry : 3/15/2001 carol : 2/13/2001 mgross : 5/26/2000 alopez : 7/31/1998 terry : 7/30/1998 terry : 5/29/1998 carol : 5/18/1998 terry : 5/18/1998 alopez : 5/14/1998 alopez : 5/4/1998 carol : 4/13/1998 terry : 3/30/1998 alopez : 3/23/1998 terry : 3/19/1998 terry : 10/13/1997 alopez : 9/5/1997 alopez : 7/10/1997 alopez : 5/19/1997 terry : 5/16/1997 terry : 2/6/1997 jamie : 12/6/1996 terry : 12/4/1996 mark : 11/22/1996 terry : 11/7/1996 mark : 7/22/1996 terry : 6/11/1996 terry : 6/7/1996 terry : 5/30/1996 mark : 2/2/1996 terry : 1/26/1996 mark : 10/12/1995 terry : 7/18/1994 jason : 7/5/1994 davew : 6/8/1994 warfield : 4/7/1994 pfoster : 3/25/1994

Table of Contents - +107730

External Links:

Genome

DNA

Protein

Gene Info

Clinical Resources

Variation

Animal Models

Cellular Pathways

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