Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1)

Abstract

Bardet-Biedl syndrome (BBS) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. Patients with BBS are also at increased risk for diabetes mellitus, hypertension, and congenital heart disease. BBS is known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although these loci were all mapped on the basis of an autosomal recessive mode of inheritance, it has recently been suggested-on the basis of mutation analysis of the identified BBS2, BBS4, and BBS6 genes-that BBS displays a complex mode of inheritance in which, in some families, three mutations at two loci are necessary to manifest the disease phenotype. We recently identified BBS1, the gene most commonly involved in Bardet-Biedl syndrome. The identification of this gene allows for further evaluation of complex inheritance. In the present study we evaluate the involvement of the BBS1 gene in a cohort of 129 probands with BBS and report 10 novel BBS1 mutations. We demonstrate that a common BBS1 missense mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. We show that the BBS1 gene is highly conserved between mice and humans. Finally, we demonstrate that BBS1 is inherited in an autosomal recessive manner and is rarely, if ever, involved in complex inheritance.

Figure 1

Haplotype analysis of the BBS1 locus. A, Summary of the haplotype analysis of 41 chromosomes carrying the M390R mutation. The number of times each haplotype was observed is shown below each haplotype. Differences from the conserved haplotype are indicated in red. Of the 41 chromosomes, 19 correspond to a single haplotype, and 38/41 chromosomes differ at no more than one marker. B, Haplotype analysis of seven chromosomes carrying a non-M390R mutation in individuals of northern European descent. Differences from the M390R-associated haplotype are indicated in red. C, Haplotype analysis of the three disease-associated alleles identified in the Puerto Rican population. Differences from the M390R-associated haplotype are indicated in red. D, Ten non–disease-associated haplotypes from Puerto Rican BBS1 heterozygous individuals. Differences from the M390R-associated haplotype are indicated in red. WT = wild type.

Figure 2

Evolutionary conservation of BBS1. A, Alignment of human BBS1 amino acid sequence with mouse Bbs1. Identical amino acids are shaded in black and conserved amino acids are shaded in gray. B, Alignment of human (Hsa) BBS1 peptide sequence and mouse (Mmu), bovine (Bta), zebrafish (Dre), and honeybee (Ame) peptide sequences surrounding the methionine at position 390 (indicated by an arrow).