Bardet-Biedl Syndrome 3

A number sign (#) is used with this entry because Bardet-Biedl syndrome-3 (BBS3) is caused by homozygous mutation in the ARL6 gene (608845) on chromosome 3q11.

Description

BBS3 is a rare autosomal recessive disorder characterized by retinal dystrophy, polydactyly, renal structural abnormalities, and history of obesity. Although mental retardation has been considered part of the BBS phenotype, several patients with BBS3 and normal intelligence have been reported. Additionally, the obesity in several BBS3 patients has been reversible with caloric restriction and exercise (Young et al., 1998; Ghadami et al., 2000).

For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900).

Clinical Features

Sheffield et al. (1994) studied a highly consanguineous 5-generation Bedouin family from the Negev region of Israel with 12 affected members with Bardet-Biedl syndrome. This family had been reported by Kwitek-Black et al. (1993) as Family 2. All but one of the patients were markedly obese, and hypogenitalism was evident in all male patients. All patients had polydactyly. All patients over the age of 1 year showed evidence of mental retardation and retinitis pigmentosa. One patient had unilateral renal hypoplasia, a second had absent right kidney, and a third had a unilateral dilated renal pelvis. Echocardiography revealed tricuspid regurgitation in 1 patient and hypertrophy of the interventricular septum in another.

Sheffield et al. (1994) reported that the clinical features of Bedouin families with BBS2 (615981) 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.

Mapping

In a large highly consanguineous Bedouin kindred with Bardet-Biedl syndrome (Kwitek-Black et al., 1993), Sheffield et al. (1994) used linkage analysis to map the phenotype to an 11-cM region between D3S1254 and D3S1302.

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.

Beales et al. (2001) refined the BBS3 critical interval to 2 cM (1.1 Mb) between D3S1603 and D3S1251.

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; 615982), and 16 (BBS2; 615981). 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.

Molecular Genetics

In the Israeli Bedouin family with BBS3 originally described by Kwitek-Black et al. (1993) and Sheffield et al. (1994), Chiang et al. (2004) detected homozygosity for a nonsense mutation in exon 7 of the ARL6 gene (R122X; 608845.0001).

In an affected member of the Newfoundland family with BBS3 studied by Young et al. (1998), Fan et al. (2004) found a homozygous missense mutation in the ARL6 gene (G169A; 608845.0002). Fan et al. (2004) also found homozygous mutation in ARL6 in 3 other BBS3 families.

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.