- Bardet-Biedl syndrome 11
- Bardet-Biedl syndrome 7
- Bardet-Biedl syndrome 10
- Bardet-Biedl syndrome 6
- Bardet-Biedl syndrome 8
- Bardet-Biedl syndrome 2
- Bardet-Biedl syndrome 3
- Bardet-Biedl syndrome 1
- Bardet-Biedl syndrome 4
- Bardet-Biedl syndrome 12
- Bardet-Biedl syndrome
- Chang Davidson Carlson syndrome
- Bardet-Biedl syndrome 9
- Bardet-Biedl syndrome 5
#209900
ICD+
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| BARDET-BIEDL SYNDROME; BBS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BARDET-BIEDL SYNDROME 1, INCLUDED; BBS1, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BARDET-BIEDL SYNDROME 2, INCLUDED; BBS2, INCLUDED BARDET-BIEDL SYNDROME 3, INCLUDED; BBS3, INCLUDED BARDET-BIEDL SYNDROME 4, INCLUDED; BBS4, INCLUDED BARDET-BIEDL SYNDROME 5, INCLUDED; BBS5, INCLUDED BARDET-BIEDL SYNDROME 6, INCLUDED; BBS6, INCLUDED BARDET-BIEDL SYNDROME 7, INCLUDED; BBS7, INCLUDED BARDET-BIEDL SYNDROME 8, INCLUDED; BBS8, INCLUDED BARDET-BIEDL SYNDROME 9, INCLUDED; BBS9, INCLUDED BARDET-BIEDL SYNDROME 10, INCLUDED; BBS10, INCLUDED BARDET-BIEDL SYNDROME 11, INCLUDED; BBS11, INCLUDED BARDET-BIEDL SYNDROME 12, INCLUDED; BBS12, INCLUDED BARDET-BIEDL SYNDROME 13, INCLUDED; BBS13, INCLUDED BARDET-BIEDL SYNDROME 14, INCLUDED; BBS14, INCLUDED BARDET-BIEDL SYNDROME 15, INCLUDED; BBS15, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because Bardet-Biedl syndrome is a genetically heterogeneous disorder. BBS1 is associated with mutations in a gene on chromosome 11q13 (209901); BBS2, with mutations in a gene on 16q21 (606151); BBS3, with mutations in the ARL6 gene on 3p12-q13 (608845). BBS4 is caused by mutation in a gene on 15q22.3 (600374); BBS5, by mutation in a gene on 2q31 (603650); BBS6, by the MKKS gene on 20p12 (604896), mutations in which also cause McKusick-Kaufman syndrome (236700); BBS7, by mutation in a gene on 4q27 (607590). BBS8 is caused by mutation in the TTC8 gene on chromosome 14q32.11 (608132); BBS9, by mutation in a gene on 7p14 (607968); BBS10, by mutation in a gene on 12q (610148); BBS11, by mutation in the TRIM32 gene on 9q33.1 (602290); BBS12, by mutation in a gene on 4q27 (610683). BBS13 is caused by mutation in the MKS1 gene (609883) on chromosome 17q23, mutations in which also cause Meckel syndrome-1 (249000). BBS14 is caused by mutation in the CEP290 gene (610142) on 12q21.3, mutations in which also cause Meckel syndrome-4 (611134) and several other disorders. BBS15 is caused by mutation in the C2ORF86 gene (613580), which encodes a homolog of the Drosophila planar cell polarity gene 'fritz.' The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had been originally thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa, RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal abnormalities appear to have a high frequency in the Bardet-Biedl syndrome (Alton and McDonald, 1973). Klein (1978) observed 57 cases of Bardet-Biedl syndrome in Switzerland. Fifteen affected individuals occurred in one inbred pedigree and 7 in a second. Pagon et al. (1982) reported a 12-year-old boy with the Bardet-Biedl syndrome (retinal dystrophy, polydactyly, mental retardation, and mild obesity) who died of renal failure and was found to have hepatic fibrosis. They reviewed both earlier reported cases and other autosomal recessive entities that combine retinal dystrophy, hepatic fibrosis and nephronophthisis. Harnett et al. (1988) evaluated 20 of 30 patients with Bardet-Biedl syndrome identified from ophthalmologic records in Newfoundland. All had some abnormality in renal structure, function, or both. Most had minor functional abnormalities and a characteristic radiologic appearance, but to date (the mean age was 31 years) only 3 of the 20 had end-stage renal disease, with 2 requiring maintenance hemodialysis. Half the subjects had hypertension. Calyceal clubbing or blunting was evident in 18 of 19 patients studied by intravenous pyelography; 13 had calyceal cysts or diverticula. Of the 19 patients, 17 had lobulated renal outlines of the fetal type. Green et al. (1989) examined 32 patients with Bardet-Biedl syndrome for some or all of the cardinal manifestations of the disorder. Of 28 patients examined, all had severe retinal dystrophy, but only 2 had typical retinitis pigmentosa. Polydactyly was present in 18 of 31 patients; syndactyly, brachydactyly, or both were present in all patients. Obesity was present in all but 1 of 25 patients. Only 13 of 32 patients were considered mentally retarded. Scores on verbal subsets of intelligence were usually lower than scores on performance tasks. Of 8 men, 7 had small testes and genitalia, which was not due to hypogonadotropism. All 12 women studied had menstrual irregularities and 3 had low serum estrogen levels (1 of these had hypogonadotropism and 2 had primary gonadal failure). Diabetes mellitus was present in 9 of 20 patients. Renal structural or functional abnormalities were present in all 21 patients studied, and 3 patients had end-stage renal failure. Gershoni-Baruch et al. (1992) emphasized the occurrence of cystic kidney dysplasia in Bardet-Biedl syndrome. They commented on the fact that the combination of cystic kidney dysplasia and polydactyly occurs also in Meckel syndrome (249000) and in the short rib-polydactyly syndromes (e.g., 263530), and that usually these syndromes are easy to differentiate. They observed 3 sibs with cystic kidney dysplasia and polydactyly who were thought to have Meckel syndrome until extinguished responses on electroretinography were detected in one of them, aged 3.5 years. In 19-year-old female twins and their 22-year-old sister, Chang et al. (1981) described hypogonadotropic hypogonadism with primary amenorrhea and lack of secondary sexual development, associated with retinitis pigmentosa. Stoler et al. (1995) described 2 unrelated girls with Bardet-Biedl syndrome who also had vaginal atresia. A similar association was suggested in reports of 11 BBS females who had structural genital abnormalities (some of which were missed in childhood), including persistent urogenital sinus; ectopic urethra; hypoplasia of the uterus, ovaries, and fallopian tubes; uterus duplex; and septate vagina. Mehrotra et al. (1997) observed 2 sisters with the Bardet-Biedl syndrome, 1 of whom had congenital hydrometrocolpos. This infant also had tetramelic postaxial polydactyly, making the diagnosis of Kaufman-McKusick syndrome (236700) a possibility in the neonatal period. However, as a teenager she was evaluated for poor vision and found to have mental deficiency, obesity, poor visual acuity, end gaze nystagmus, tapetoretinal degeneration, and extinguished electroretinogram. Her older sister had similar eye complaints; she likewise was born with tetramelic postaxial polydactyly and was also mentally retarded. David et al. (1999) reported 9 patients who, because of the presence of vaginal atresia and postaxial polydactyly, were diagnosed in infancy with McKusick-Kaufman syndrome; these patients later developed obesity and retinal dystrophy and were diagnosed with Bardet-Biedl syndrome. David et al. (1999) suggested that the phenotypic overlap between McKusick-Kaufman syndrome and Bardet-Biedl syndrome is a diagnostic pitfall, and that all children in whom a diagnosis of McKusick-Kaufman syndrome is made in infancy should be reevaluated for retinitis pigmentosa and other signs of Bardet-Biedl in later childhood. In Bedouin families in the Negev region of Israel, presumably the same kindreds as those studied by Kwitek-Black et al. (1993), Elbedour et al. (1994) performed echocardiographic evaluations of cardiac involvement in BBS. They stated that they found cardiac involvement in 50% of cases, justifying inclusion of echocardiographic examination in the clinical evaluation and follow-up of these patients. However, their Table 1 gives echocardiographic abnormality in only 7 of 22 cases and these included 1 case of bicuspid aortic valve, 1 case of mild thickening of the interventricular septum, 1 case of 'moderate tricuspid regurgitation,' and 1 case of mild pulmonic valve stenosis. The occurrence of renal abnormality in 11 of the 22 patients on kidney ultrasonography was somewhat more impressive than the cardiac involvement. Islek et al. (1996) described a boy with postaxial polydactyly and Hirschsprung disease (142623) found at the age of 3 months. Follow-up examination at the age of 7 years showed obesity, mental retardation, retinitis pigmentosa, microphallus, and cryptorchidism. The diagnosis of Bardet-Biedl syndrome was established. According to Islek et al. (1996), 2 other cases of association of Bardet-Biedl syndrome and Hirschsprung disease have been reported. Beales et al. (1999) reported a study of 109 BBS patients and their families. Average age at diagnosis was 9 years. Postaxial polydactyly was present in 69% of patients at birth, but obesity did not begin to develop until approximately 2 to 3 years of age, and retinal degeneration did not become apparent until a mean age of 8.5 years. As a result of their study, Beales et al. (1999) proposed a set of diagnostic criteria based on primary and secondary features. They suggested the use of the term polydactyly-obesity-kidney-eye syndrome in recognition of what they described as the phenotypic overlap between BBS and Laurence-Moon syndrome. In 2 patients with Bardet-Biedl syndrome, Lorda-Sanchez et al. (2000) identified 2 uncommon manifestations: situs inversus in one and Hirschsprung disease in the other. They were unable to determine which of the 5 forms of BBS known at that time was present in these cases. Cox et al. (2003) examined the electrophysiologic responses of carriers of BBS. All carriers had decreased corneal positive potential and 60% had a decreased b-wave sensitivity. The authors postulated that the site of the primary defect in the BBS rod pathway appeared to be proximal to the rod outer segments, most likely before the rod-bipolar cell synapse. Kulaga et al. (2004) showed that individuals with BBS have partial or complete anosmia (107200). To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, they examined mice with deletions of Bbs1 or Bbs4 (600374) genes. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Iannaccone et al. (2005) described decreased olfaction in 2 individuals from a 5-generation Italian family with BBS4 previously reported by Mykytyn et al. (2001) (see 600374.0002). They concluded that the BBS4 gene plays a role in olfaction, supporting the hypothesis that ciliary dysfunction is an important aspect of BBS pathogenesis. They suggested that the spectrum of clinical manifestations associated with BBS be broadened to include decreased olfaction. Deffert et al. (2007) reported 2 brothers, born of consanguineous Algerian parents, with clinical features of BBS although no causative mutation was identified in the BBS1 through BBS10 genes. In addition to diagnostic criteria, both boys had insertional polydactyly and situs inversus. One brother developed cone-rod dystrophy in childhood and the other developed progressive vision loss at age 15 years resulting in blindness by 18 years. By detailed neurologic examination of 9 BBS patients, Tan et al. (2007) observed a noticeable decrease in peripheral sensation affecting all modalities in most patients. Tan et al. (2007) concluded that this may be an underrecognized component of the disorder. Relationship to Laurence-Moon Syndrome There has been longstanding uncertainty as to the relationship between the Laurence-Moon syndrome (245800) and the Bardet-Biedl syndrome. Solis-Cohen and Weiss (1925) lumped them together as the Laurence-Biedl syndrome. Ammann (1970) concluded that the patients of Laurence and Moon had a distinct disorder with paraplegia and without polydactyly and obesity. As suggested by the study of Ammann (1970), residual heterogeneity may exist even after the Laurence-Moon syndrome is separated; for example, Biemond syndrome II (iris coloboma, hypogenitalism, obesity, polydactyly, and mental retardation; 213350) and Alstrom syndrome (retinitis pigmentosa, obesity, diabetes mellitus, and perceptive deafness; 203800) were considered distinct entities. Schachat and Maumenee (1982) reviewed the nosography of these and related syndromes. In a 22-year prospective cohort study of 46 patients from 26 Newfoundland families with BBS, Moore et al. (2005) found no apparent correlation of clinical or dysmorphic features with genotype. They reported that of 2 patients clinically diagnosed as having Laurence-Moon syndrome, one was from a consanguineous pedigree with linkage to the BBS5 gene, and the other was a compound heterozygote for mutations in the MKKS gene (604896.0007 and 604896.0008). Moore et al. (2005) concluded that the features in this population did not support the notion that BBS and LMS are distinct. The patient with mutations in the MKKS gene (NF-B5) had previously been reported by Katsanis et al. (2000) as having BBS6, thus illustrating the difficulty in distinguishing these 2 disorders. Bardet-Biedl Syndrome 1 Beales et al. (1997) observed only subtle phenotypic differences among Bardet-Biedl families mapping to the BBS1, BBS2, or BBS4 loci, the most striking of which was the finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and BBS4 groups were significantly shorter than their parents. In more than one-fourth of the pedigrees, linkage to no known locus could be established, suggesting the existence of a fifth BBS locus. Bardet-Biedl Syndrome 3 Sheffield et al. (1994) reported that the clinical features of Bedouin families with BBS2 and BBS3 were very similar. For example, all affected individuals in both kindreds showed postaxial polydactyly. The authors hypothesized that the identical phenotype resulting from different mutations at 2 separate loci might have its explanation in involvement of a ligand-receptor complex, protein subunits, or proteins involved in a common biochemical pathway. In the Newfoundland kindred of Northern European descent with BBS3 described by Young et al. (1998), the BBS3 phenotype, which includes polydactyly of all 4 extremities, mental retardation, and progression to morbid obesity, was not observed. Patients had polydactyly limited to the lower limbs, average IQ, and obesity reversible by caloric restriction and/or exercise. Ghadami et al. (2000) reported an Iranian family with BBS3 in 7 members. Linkage analysis showed that this was indeed BBS3. All patients had a history of mild to severe obesity, which was reversible in some patients by caloric restriction and exercise. All patients had pigmentary retinopathy, beginning as night blindness in early childhood and progressing toward severe impairment of vision by the end of the second decade. Polydactyly varied in limb distribution, ranging from 4-limb involvement to random involvement or even to lack of polydactyly. Six of the 7 patients were not mentally retarded. Although kidney anomaly or an adrenal mass was present in 2 patients, the fact that 1 patient had 7 children ruled out reproductive dysfunction. Comparison of clinical manifestations with those of previously reported BBS3 patients did not support any type-specific phenotypes. Bardet-Biedl Syndrome 5 Young et al. (1999) reported that in 5 affected members of a BBS5 kindred, related as sibs or first cousins in 3 sibships and of ages varying from 21 to 31 years, none had polydactyly, but all had brachydactyly and/or syndactyly. All had severe visual impairment with retinal macular changes, and in the 2 males examined, the penis was small. Bardet-Biedl Syndrome 10 Putoux et al. (2010) identified homozygous or compound heterozygous mutations in the C12ORF58 gene (see, e.g., 610148.0001; 610148.0006) in 5 of 21 patients with antenatal onset of severe renal cystic anomalies and polydactyly, without the biliary or hepatic abnormalities characteristic of Meckel syndrome (MKS; 249000). Four of the patients were fetuses between ages 21 and 26 weeks' gestation, and the fifth was a 20-year-old woman with BBS10 who was found to have hyperechogenic kidneys and polydactyly on antenatal ultrasound. The most common mutation was a 1-bp duplication (271dupT; 610148.0001), found on 6 of 10 mutant C12ORF58 alleles. The 20-year-old woman also carried a heterozygous truncating mutation in the BBS6 gene. Putoux et al. (2010) noted that the diagnosis of severe lethal BBS is suggested in utero by the findings of severe cystic kidneys and polydactyly without biliary dysgenesis or brain anomalies, and concluded that mutations in the C12ORF58 gene may account for a high percentage of such cases. Bardet-Biedl Syndrome 12 Dulfer et al. (2010) reported 2 female sibs with BBS resulting from compound heterozygous truncating mutations in the BBS12 gene. Each also carried a third heterozygous mutation in the BBS10 gene. The first patient had postaxial polydactyly type A and severe hydrometrocolpos, resulting in prolonged delivery with hypoxia and death at delivery. Examination showed atresia of the distal vagina, a dilated cervix and uterus, and cystic renal dysplasia. The second pregnancy was terminated at 15 weeks' gestation after chorionic villus sampling identified the same 3 mutations in the second fetus, which had no external features of BBS and no abnormalities of the internal genitalia, although cystic renal dysplasia was present. Dulfer et al. (2010) noted the phenotypic variability between these sibs, and suggested that hydrometrocolpos should be considered a feature in females with BBS. The authors also questioned whether the BBS10 mutation had any influence on the phenotype, since the BBS12 mutations were sufficient to cause the disorder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Katsanis et al. (2001) screened 163 BBS families for mutations in both BBS2 and BBS6 and reported the presence of 3 mutant alleles in affected individuals in 4 pedigrees. In addition, Katsanis et al. (2001) detected unaffected individuals in 2 pedigrees who carried 2 BBS2 mutations but not a BBS6 mutation. One of these was found to be homozygous by descent for a BBS1 allele, and the other was found to be homozygous by descent for a BBS4 allele. The identification of the gene most commonly mutated in individuals with BBS (BBS1; 209901) allowed Mykytyn et al. (2002) to examine the hypothesis that 3 mutated alleles are required for penetrance of the BBS phenotype (triallelic inheritance), as had been suggested by Katsanis et al. (2001). They did not find the common M390R mutation (209901.0001) in any of 12 unrelated individuals who had previously been shown to have 2 mutations in BBS2, BBS4, or BBS6 (MKKS). Moreover, complete sequencing of BBS1 in these individuals revealed no coding sequence variations. In addition, they sequenced BBS2, BBS4, and MKKS in 10 unrelated North American individuals who were homozygous with respect to the BBS1 M390R mutation. All sequence alterations identified in affected individuals were also found in controls. Although it is possible that these individuals could harbor an additional mutated allele in an unidentified gene underlying BBS, the fact that the remaining genes account for a very small proportion of Bardet-Biedl syndrome makes this unlikely. Finally, in 6 multiplex families in which affected individuals harbored BBS1 mutations, Mykytyn et al. (2002) did not detect any unaffected individuals with 2 BBS1 mutations. Thus, in the families studied by them, the disorder segregated as an autosomal recessive disease, with no evidence that BBS1 acts in triallelic inheritance. Mykytyn et al. (2003) demonstrated that the common BBS1 M390R mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. Stoetzel et al. (2006) identified homozygous mutations in the TTC8 gene (608132.0003 and 608132.0004) in 2 of 128 BBS families. One additional family had a heterozygous mutation. Stoetzel et al. (2006) concluded that mutations in the TTC8 gene account for only about 2% of BBS families. Stoetzel et al. (2006) found that the BBS10 gene (610148) was mutated in about 20% of an unselected cohort of families of various ethnic origins. Notably, they found a similar frequency of mutations among families of Middle Eastern ancestry as among those of European ancestry. Twelve of 65 (18%) families with BBS10 mutations also had mutations or recognized variants at another BBS locus, indicative of a potential epistatic interaction. In affected members of 3 sibships within a large consanguineous Lebanese kindred with BBS reported by Stoetzel et al. (2006), Laurier et al. (2006) found homozygosity for a mutation in the BBS10 gene (610148.0004). The only affected individual from a fourth sibship within this kindred was compound heterozygosity for 2 mutations in the BBS10 gene (610148.0004 and 610148.0005). In addition, 2 affected individuals from a fifth sibship within this kindred were homozygous for a mutation in the BBS2 gene (606151.0017). There was no evidence for triallelism in this kindred, although 3 different mutations in 2 different genes (BBS2 and BBS10) were found. Laurier et al. (2006) commented on the unusual finding of homozygosity and compound heterozygosity for mutations in 2 different genes within a single large consanguineous kindred. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Heterogeneity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Type 1 Bardet-Biedl syndrome (BBS1) is caused by mutation in a gene that maps to chromosome 11q13 (209901). Bardet-Biedl syndrome type 2 (BBS2) is caused by mutation in a gene that maps to chromosome 16q21 (606151). Bardet-Biedl syndrome type 3 (BBS3) is caused by mutation in the ADP-ribosylation factor (ARF)-like-6 gene (ARL6; 608845) on chromosome 3p13-p12. Bardet-Biedl syndrome type 4 (BBS4) is caused by mutation in a gene that maps to chromosome 15q22.3-q23 (600374). Bardet-Biedl syndrome type 5 (BBS5) is caused by mutation in a gene that maps to chromosome 2q31 (603650). Bardet-Biedl syndrome type 6 (BBS6) is caused by mutation in the same gene, MKKS (604896), located on 20p12, that is mutant in McKusick-Kaufman syndrome (236700). Bardet-Biedl syndrome type 7 (BBS7) is caused by mutation in a gene that maps to chromosome 4q27 (607590). Mutation in a tetratricopeptide repeat protein, TTC8 (608132), causes Bardet-Biedl syndrome type 8 (BBS8). Mutation in the parathyroid hormone-responsive gene B1 (PTHB1; 607968) causes Bardet-Biedl syndrome type 9 (BBS9). Mutation in the C12ORF58 gene (610148) causes Bardet-Biedl syndrome type 10 (BBS10). Mutation in the tripartite motif-containing protein-32 gene (TRIM32; 602290) causes Bardet-Biedl syndrome type 11 (BBS11). Mutation in the C4ORF24 gene (610683) causes Bardet-Biedl syndrome type 12. Bardet-Biedl syndrome type 13 (BBS13) is caused by mutation in the MKS1 gene (609883). Bardet-Biedl syndrome type 14 (BBS14) is caused by mutation in the CEP290 gene (610142). Bardet-Biedl syndrome type 15 (BBS15) is caused by mutation in the C2ORF86 gene (613580). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a population-based study including 93 BBS patients from 74 families of various ethnicities, Billingsley et al. (2010) determined that the chaperonin-like BBS6, BBS10, and BBD12 genes are a major contributor to the disorder. Biallelic mutations in these 3 genes were found in 36.5% of the families: 4 patients had mutations in BBS6, 19 had mutations in BBS10, and 10 had mutations in BBS12. Overall, 26 (68%) of 38 mutations were novel. Six patients had mutations present in more than 1 chaperonin-like BBS gene, and 1 patient with a very severe phenotype had 4 mutations in BBS10. The phenotypes observed were beyond the classic BBS phenotype and overlapped with characteristics of MKKS (236700), including congenital heart defect, vaginal atresia, hydrometrocolpos, and cryptorchidism, and with Alstrom syndrome (203800), including diabetes, hearing loss, liver abnormalities, endocrine anomalies, and cardiomyopathy. Muller et al. (2010) screened the BBS1 through BBS12 genes and identified pathogenic mutations in 134 (77%) of 174 BBS families: 117 families had 2 pathogenic mutations in a single gene, and 17 families had a single heterozygous mutation, 8 of which were the BBS1 recurrent mutation M390R (209901.0001). BBS1 and BBS10 were the most frequently mutated genes, each found in 32.6% of families, followed by BBS12, found in 10.4% of families. No mutations were found in BBS11, which has only been identified in 1 consanguineous family. There was a high level of private mutations, and Muller et al. (2010) discussed various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations. By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a 6-bp deletion in the BBS7 gene (607590.0004) in affected members of a family (M324) segregating Bardet-Biedl syndrome. Modifier Genes The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Putoux et al. (2011) identified 8 different heterozygous missense mutations in the KIF7 gene (611254) in 8 patients with ciliopathies, including Bardet-Biedel syndrome, Meckel syndrome (MKS; 249000), Joubert syndrome (JBTS; 213300), Pallister-Hall syndrome (PHS; 146510), and OFD6 (277170). Four of these patients had additional pathogenic mutations in other BBS genes. Rescue studies of somites in morphant zebrafish embryos demonstrated that the heterozygous KIF7 missense mutations were hypomorphs, and Putoux et al. (2011) concluded that these alleles may contribute to or exacerbate the phenotype of other ciliopathies, particularly BBS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Janssen et al. (2011) used a DNA pooling and massively parallel resequencing strategy to screen 132 individuals with BBS from 105 families. This method allowed identification of both disease-causing mutations in 29 (28%) of 105 families. Thirty-five different disease-causing mutations were identified, 18 of which were novel. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Carmi et al. (1995) compared the clinical manifestations of BBS in 3 unrelated, extended Arab-Bedouin kindreds in which linkage had been demonstrated to chromosomes 3 (BBS3), 15 (BBS4), and 16 (BBS2). Observed differences included the limb distribution of the postaxial polydactyly and the extent and age-association of obesity. It appeared that the chromosome 3 locus is associated with polydactyly of all 4 limbs, while polydactyly of the chromosome 15 type is mostly confined to the hands. The chromosome 15 type is associated with early-onset morbid obesity, while the chromosome 16 type appears to present the 'leanest' end of BBS. Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0010) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations, including BBS. BBS Gene Heterozygosity On the basis of a study of 75 relatives in 5 generations of the extended family of 2 adult Bardet-Biedl sibs, Croft and Swift (1990) suggested that heterozygotes have an increased frequency of obesity, hypertension, diabetes mellitus, and renal disease. They pointed out that homozygotes have hepatic disease. Croft et al. (1995) studied obesity and hypertension among nonhomozygous relatives of BBS patients, hypothesizing that BBS heterozygotes might be predisposed to these conditions. Among 34 parents of BBS homozygotes (obligate heterozygotes), a proportion of severely overweight fathers (26.7%) were significantly higher than that in comparably aged U.S. white males (8.9%). They concluded that the BBS gene may predispose male heterozygotes to obesity. If heterozygotes represent 1% of the general population, they estimated that approximately 2.9% of all severely overweight white males carry a single BBS gene. The BBS parents of both sexes were also significantly taller than U.S. white men and women of comparable age. Beales et al. (1999) found renal cell adenocarcinomas in 3 parents of individuals with BBS, and congenital renal malformations in a number of others. They suggested that these findings may be a consequence of heterozygosity for disease-causing mutations in BBS genes. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a study of 19 BBS families of mixed but predominantly European ethnic origin, Bruford et al. (1997) obtained results showing that an estimated 36 to 56% of the families were linked to 11q13. A further 32 to 35% of the families were linked to 15q22.3-q23. Three consanguineous families showed homozygosity for 3 adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis reported a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to 16q21 was observed in 24 to 27% of families. A fourth group of families, estimated at 8%, were unlinked to all 3 of the above loci. Bruford et al. (1997) found no evidence of linkage to markers on chromosome 3, corresponding to the BBS3 locus, or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with Bardet-Biedl syndrome and a t(2;17) translocation reported by Dallapiccola (1971). The prevalence of BBS in Newfoundland is approximately 10-fold greater than in Switzerland (1 in 160,000) and similar to the prevalence among the Bedouin of Kuwait (1 in 13,500). Woods et al. (1999) performed a population-based genetic survey of 17 BBS families in the island portion of the province of Newfoundland. The families contained a total of 36 well-documented affected individuals; 12 families had 2 or more affected persons. Linkage at each of the 4 then-known loci was tested with 2-point linkage and haplotype analysis. Three of the kindreds showed linkage to 11q (BBS1), 1 to 16q (BBS2), and 1 to 3p (BBS3). The BBS3 family was the first to be identified in a population of northern European descent. Six families remained undetermined because of poor pedigree structure or inconclusive haplotype analyses. Six families were excluded from all 4 then-known BBS loci, including BBS4. In a study of 7 Saudi Arabian BBS families, Safieh et al. (2010) demonstrated that homozygosity mapping was an efficient approach to identifying causative mutations, because it allowed them to sequence only 1 gene per family and find 7 novel mutations, respectively: 3 in the BBS1 gene, 3 in the BBS3 gene, and 1 in the BBS4 gene. Six of the families displayed the typical constellation of findings for BBS, which varied in frequency between families but were highly consistent within families, suggesting that modifiers appear to play only a minor role in the expressivity of BBS. In the remaining family, previously reported by Aldahmesh et al. (2009), a homozygous BBS3 mutation (608845.0006) segregated with nonsyndromic autosomal recessive RP (RP55; 613575). Compared with earlier reports, Safieh et al. (2010) stated that their data were consistent with a trend towards milder severity in patients with BBS3 mutations, since all cases of documented normal male fertility or lack of cognitive impairment belonged to this category. In addition, atopy appeared to be a common clinical feature that was not restricted to a specific genotype, and none of their patients reported a history of hyposmia, suggesting that this is an uncommon finding. Harville et al. (2010) independently used homozygosity mapping in a worldwide cohort of 45 BBS families to identify 17 causative homozygous mutations in 20 families, in the BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS10, and BBS12 genes. Three mutations occurred in 2 unrelated families each, and 11 of the 17 mutations were novel; none of the mutations were found in more than 90 ethnically matched controls. Harville et al. (2010) concluded that whole-genome homozygosity mapping followed by direct sequencing is an effective alternative means of identifying causative mutations in disorders of striking genetic heterogeneity such as BBS. Linkage to 11q13 (BBS1) Leppert et al. (1994) performed linkage analysis in 31 multiplex BBS families and reported linkage with 2 markers on 11q, PYGM (608455) and an anonymous marker, D11S913. The homozygosity testing demonstrated genetic heterogeneity within the set of families. The confidence interval for BBS1, based on a 1 lod difference, extended approximately 1 cM proximal to PYGM and 2 cM distal to PYGM. PYGM is located in band 11q13. Leppert et al. (1994) stated that they had seen families unlinked to either chromosome 16 (BBS2) or chromosome 11. Beales et al. (1997) studied 18 families with 2 or more members affected with Bardet-Biedl syndrome, noting the presence of both major and minor manifestations. They performed linkage studies in the hope of finding phenotypic differences between the 4 linkage categories identified to that time. Eight of the families (44%) were found to be linked to 11q13 (BBS1), and 3 (17%) were linked to 16q21 (BBS2). Only 1 family was linked to 15q22 (BBS4; 600374), and none were linked to 3p12 (BBS3; 608845). They concluded that BBS1 is the major locus among white Bardet-Biedl patients and that BBS3 is extremely rare. Only subtle phenotypic differences were observed, the most striking of which was the finding of taller affected offspring compared with their parents in the BBS1 category. Affected subjects in the BBS2 and BBS4 groups were significantly shorter than their parents. In more than one-fourth of the pedigrees, linkage to no known locus could be established, suggesting the existence of a fifth BBS locus. Katsanis et al. (1999) collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in 2 consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. Young et al. (1999) used linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to reduce significantly the BBS1 critical region. Extensive haplotype analysis in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype. The LD data suggested that the BBS1 gene lies in a 1-Mb, sequence-ready region on 11q13. Linkage to 16q21 (BBS2) Kwitek-Black et al. (1993) performed linkage studies in a large inbred Bedouin family from the Negev region of Israel. All 9 affected persons had polydactyly and pigmented retinopathy. Linkage and the candidate gene approach were used to exclude all known autosomal pigmented retinopathy loci. Thereafter, a genomewide search for linkage was conducted using short tandem repeat polymorphisms (STRPs). By this approach, they identified linkage of the BBS locus to markers that mapped to 16q21. Maximum likelihood calculations for 2-point linkage between D16S408 and the disease phenotype resulted in Z = 4.2 at theta = 0.0. A multilocus lod score of 5.3 was observed. By demonstrating homozygosity in all affected individuals for the same allele of marker D16S408, further support for linkage was found, and the utility of homozygosity mapping using inbred families was demonstrated. In a second family with BBS from a different Bedouin tribe and unrelated to the first family, linkage to the same chromosome 16 markers was excluded over a stretch of at least 20 cM centered on marker D16S408. The symbol BBS2 was used for the locus on chromosome 16 and BBS1 for the non-chromosome 16 locus (McAlpine, 1994). Nishimura et al. (2001) used physical mapping and sequence analysis to identify the BBS2 gene at 16q21. An open reading frame of 2,163 bp was distributed over 17 exons. The gene is evolutionarily conserved and displays a wide pattern of tissue expression, including brain, kidney, adrenal gland, and thyroid gland. Mutations in the gene were identified in 3 of 18 unrelated BBS families. Linkage to 3p13 (BBS3) Using conventional linkage analysis of an inbred Bedouin kindred, Sheffield et al. (1994) demonstrated linkage of the disease locus to chromosome 3 in a 11-cM region between D3S1254 and D3S1302 (loci identified by short tandem repeat polymorphisms; STRPs). They commented that the locus was not near any of the known human retinopathy loci and was not in a region of syntenic homology with any known mouse obesity locus. They thus demonstrated that there are 2 genetic forms of BBS in the Bedouin population of the Middle East, one determined by a chromosome 16 gene (BBS2; 606151) and one determined by a chromosome 3 gene (BBS3). Linkage of Bardet-Biedl syndrome to chromosome 3 in the kindred studied by Sheffield et al. (1994) was supported by a lod score of 7.52 at theta = 0.0, as well as by the observation of homozygosity in highly informative markers across the candidate region in affected individuals. From the location of the markers it was concluded that the BBS3 locus is situated in 3p13-p12. This finding in a highly inbred kindred permitted Sheffield et al. (1994) to test an efficient strategy for linkage mapping. The approach consisted of pooling equal amounts of DNA from each affected individual in the kindred. The affected DNA pool was then used as a template for PCR with primers for genetic markers. Markers not linked to the genetic disorder had multiple alleles in the pool sample, whereas linked markers demonstrated a shift in allele frequency towards a single allele. A marker completely linked to a recessive disease showed a single allele when amplified from DNA pooled from affected individuals from a single pedigree. This approach required that a single common progenitor contributed the disease allele to all affected individuals. Sheffield et al. (1994) suggested that the pooling strategy should be well suited not only for studying recessive disorders in genetically isolated populations but also for dominant disorders in other instances where there is identity by descent. Quantitative trait loci (QTLs) in genetically isolated populations could be studied by comparing 2 pools consisting of individuals displaying the 2 extremes of the phenotype. Young et al. (1998) described a Newfoundland kindred of Northern European descent with BBS and narrowed the chromosome 3p critical region to 6 cM between D3S1595 and D3S1753. Linkage to 15q22.3 (BBS4) Carmi et al. (1995) used a DNA pooling approach with DNA samples from a highly inbred Bedouin kindred to identify a Bardet-Biedl syndrome locus on chromosome 15. Homozygosity mapping using pooled DNA samples assumes that all or most of the affected individuals share a common chromosomal region inherited from a common ancestral founder. The pooled DNA was used as a PCR template with primers for short tandem repeat polymorphisms (STRPs). Pools consisting of DNA from unaffected sibs and parents of affected individuals were used as controls. Markers not linked to the disease locus are expected to show similar allele frequencies in the affected and controlled pools as a result of independent assortment. On the other hand, STRPs in linkage disequilibrium with the disease phenotype show a shift in allele frequencies toward a single homozygous allele in the affected DNA pool. Following identification of linked loci by linkage disequilibrium (homozygosity mapping), individual members of the pedigree were genotyped using the STRP markers. All 8 STRPs resulted in a positive lod score. Carmi et al. (1995) commented that the locus on chromosome 15 in the q22.3-q23 region is not near any of the known human retinopathy loci and is not in the region of syntenic homology with any of the known mouse obesity loci. The phenotype of the patients in the chromosome 15 kindred was very similar to that described for the previously linked loci. Identification of the genes involved in these 4 genetic forms of BBS may aid in the understanding of common disorders such as obesity, hypertension, and diabetes. Linkage to 2q31 (BBS5) By a genomewide scan of pooled DNA samples using microsatellite markers in a family with BBS, Young et al. (1999) demonstrated that the BBS5 locus maps to 2q31. The 2q31 region is close to the HOXD gene cluster (142987), but refined mapping of the recombinant ancestral chromosome excluded all genes within that cluster as candidates for BBS5. Linkage to 20p12 (BBS6) Slavotinek et al. (2000) and Katsanis et al. (2000) independently identified a form of Bardet-Biedl syndrome caused by mutations in the MKKS gene, a chaperonin-like gene in which mutations associated with McKusick-Kaufman syndrome had been found. Slavotinek et al. (2000) sought mutations in the MKKS gene because of phenotypic similarities between McKusick-Kaufman syndrome and Bardet-Biedl syndrome. McKusick-Kaufman syndrome includes hydrometrocolpos, postaxial polydactyly, and congenital heart disease, with autosomal recessive inheritance. Bardet-Biedl syndrome is likewise an autosomal recessive disorder and is characterized by obesity, retinal dystrophy, polydactyly, learning difficulties, hypogenitalism, and renal malformations, with secondary features that include diabetes mellitus. Five distinct forms of Bardet-Biedl syndrome, BBS1-5, had been distinguished on the basis of linkage analysis. Katsanis et al. (2000) performed a genome screen in BBS families from Newfoundland in which BBS1 types 1 through 5 had been excluded and found linkage to a region of chromosome 20 encompassing the MKKS gene. Beales et al. (2001) collected a cohort of 163 BBS pedigrees from diverse ethnic backgrounds and evaluated them for mutations in the MKKS gene and for potential assignment of the disorder to any of the other known BBS loci. Using a combination of mutation and haplotype analysis, they described a spectrum of BBS6 alterations that are likely to be pathogenic; proposed substantially reduced critical intervals for BBS2 (209900) on 16q21, BBS3 (608845) on 3p, and BBS5 (603650) on 2q; and presented evidence for the existence of at least one more BBS locus, bringing the total to 7. The data suggested that BBS6 is a minor contributor to the syndrome and that some BBS6 alleles may act in conjunction with mutations at other BBS loci to cause or modify the BBS phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Population Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Farag and Teebi (1988) concluded that the frequency of both the Bardet-Biedl and the Laurence-Moon syndromes is increased in the Arab population of Kuwait. Farag and Teebi (1989) pointed to a high frequency of the Bardet-Biedl syndrome among the Bedouin; the estimated minimum prevalence was 1 in 13,500. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathogenesis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ansley et al. (2003) demonstrated that BBS is probably caused by a defect of the basal body of ciliated cells. The TTC8 gene (608132), mutations in which are responsible for BBS8, encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In 1 family a homozygous null BBS8 mutation (608132.0002) led to BBS with randomization of left-right body axis symmetry, a defect of the nodal cilium. Ansley et al. (2003) showed that TTC8 localizes to centrosomes and basal bodies and colocalizes with gamma-tubulin (see 191135), BBS4 (600374), and PCM1 (600299). Furthermore, Ansley et al. (2003) found that all available C. elegans BBS homologs are expressed exclusively in ciliated neurons and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport. Bardet-Biedl syndrome is thought to result largely from ciliary dysfunction, because loss-of-function mutations in the genes of C. elegans homologous to BBS7 (607590) and BBS8 (608132) compromise cilia structure and function, and RNA interference of Chlamydomonas BBS5 (603650) results in the loss of flagella. Notably, all known C. elegans bbs genes are expressed exclusively in cells with cilia, owing to the presence of a DAF-19 RFX transcription factor binding site (X box) in their promoters. Fan et al. (2004) hypothesized that the C. elegans ortholog of the human BBS3 gene would also contain this regulatory element, which would allow them to identify candidates from among the more than 90 genes that map to the BBS3 critical interval. One of 3 genes containing the X box in their promoters that determine exclusive expression in cells with cilia was ARL6 (608845), making it a good candidate for the BBS3 gene. Fan et al. (2004) indeed found mutations in ARL6 segregating with BBS in 4 independent families. Badano et al. (2006) identified MGC1203 (610162), also known as CCDC28B, as contributing epistatic alleles to Bardet-Biedl syndrome. Marion et al. (2009) found that human preadipocytes transiently formed a primary cilium that carried Wnt (see WNT1; 164820) and hedgehog (see SHH; 600725) receptors during preadipocyte differentiation. Immunohistochemical showed that both BBS10 and BBS12 localized to the basal body of this primary cilium. Knockdown of BBS10 and BBS12 expression by RNA interference reduced the number of ciliated cells and increased the amount of unphosphorylated active GSK3 (see GSK3A; 606784), a key regulator of adipogenesis that is repressed by Wnt signaling. Furthermore, differentiation of BBS10 and BBS12 patient fibroblasts into fat-accumulating cells was associated with increased triglyceride content compared with control cells. Marion et al. (2009) concluded that a primary dysfunction of adipogenesis results in the development of obesity in BBS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kulaga et al. (2004) examined mice with deletions of the Bbs1 or Bbs4 (600374) genes. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Ross et al. (2005) showed that mice with mutations in genes involved in Bardet-Biedl syndrome share phenotypes with planar cell polarity (PCP) mutants including open eyelids, neural tube defects, and disrupted cochlear stereociliary bundles. Furthermore, they identified genetic interactions between BBS genes and a PCP gene in both mouse (LTAP, also called VANGL2; 600533) and zebrafish (vangl2). In zebrafish, the augmented phenotype resulted from enhanced defective convergent extension movements. Ross et al. (2005) also showed that VANGL2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggested that cilia are intrinsically involved in planar cell polarity processes. Stoetzel et al. (2006) modeled loss of function of the BBS10 gene (610148) in zebrafish. Suppression of the maternal bbs10 message caused shortening of the rostrocaudal body axis; dorsal thinning, broadening, and kinking of the notochord; elongation of the somites; and decreased somitic definition and symmetry. Mild suppression of bbs10 exacerbated the phenotypes of other bbs morphants. Eichers et al. (2006) generated a mouse model of BBS4 by targeted inactivation of the murine Bbs4 gene. Although the mice were initially runted compared to wildtype, they later became obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal liver profiles, signs of liver dysfunction, and increased insulin and leptin levels similar to the metabolic syndrome (see 605552). Affected mice also developed age-dependent retinal dystrophy and displayed anxiety-related behavior. Birth defects, such an neural tube defects, occurred rarely. Stoetzel et al. (2007) suppressed BBS6 (604896), BBS10, and BBS12 (610683) in zebrafish and observed gastrulation-movement defects characteristic of other BBS morphants. Suppression of each of these chaperonin-like molecules yielded highly overlapping phenotypes, but simultaneous suppression of these 3 genes, which comprise a subfamily, grossly exaggerated the penetrance and expressivity of these phenotypes. Stoetzel et al. (2007) suggested that this effect might underlie either some partial functional redundancy within the subfamily or might reflect the progressive loss of pericentriolar function. Davis et al. (2007) generated a knockin mouse model of the BBS1 M390R mutation (209901.0001). Mice homozygous for M390R recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. Morphologic evaluation of Bbs1 mutant brain revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Ultrastructural examination of the ependymal cell cilia that lined the enlarged third ventricle of Bbs1 mutant brains showed that, whereas the 9+2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Davis et al. (2007) concluded that the M390R mutation does not affect axonemal structure, but it may play a role in regulation of cilia assembly and/or function. By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and Bbs4-null mice demonstrated behavioral deficits in thermosensation and mechanosensation associated with alterations in the trafficking of the thermosensory channel Trpv1 (602076) and the mechanosensory channel Stoml3 (608327) within sensory neurons. The findings were replicated in C. elegans lacking Bbs7 or Bbs8. Detailed examination of 9 patients with BBS showed a noticeable decrease in peripheral sensation in most of them. Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the M390R mutation in Bbs1, Shah et al. (2008) showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness. Seo et al. (2009) showed that BBS proteins were required for leptin receptor (LEPR; 601007) signaling in the hypothalamus in mice. Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice were resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin (LEP; 164160) levels and obesity. Activation of hypothalamic Stat3 (102582) by leptin was significantly decreased in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. In contrast, downstream melanocortin receptor (see 155555) signaling was unaffected, indicating that Lepr signaling was specifically impaired in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. Impaired Lepr signaling in BBS mice was associated with decreased Pomc (176830) gene expression. The human BBS1 protein physically interacted with LEPR, and loss of BBS proteins perturbed LEPR trafficking in human cells. Seo et al. (2009) concluded that BBS proteins mediate LEPR trafficking and that impaired LEPR signaling may underlie energy imbalance in BBS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Bardet (1920); Beales et al. (1999); Bell (1958); Biedl (1922); Chanmugam et al. (1977); Ciccarelli and Vesell (1961); Haning et al. (1980); Kalbian (1956); Katsanis et al. (2001); Solis-Cohen and Weiss (1924); Toledo et al. (1977) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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