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.

Testing for triallelism: analysis of six BBS genes in a Bardet–Biedl syndrome family cohort

“…25,27 Herein, in agreement with the previous reports, 5/6 (80%) families, with BBS1 mutations, were found to carry the M390R mutation (two as homozygous alleles and three as heterozygous alleles) representing the most common mutation found in this series of BBS patients. The M390R mutation is considered to be an ancient mutation as suggested by haplotype analysis and was described exclusively in patients of European descent.…”

“…The E549X mutation was previously reported in the homozygous state in Puerto-Rican families and also in the compound heterozygous state with the M390R mutation. 10,25 The M390R mutation is associated with E384X in exon 12 in family I.22. The proband of family I.23 carries the M390R mutation and a c.479G4A change that predicts a missense mutation (R160Q) affecting a highly conserved residue, but which also most likely alters the donor splice site of exon 5, as it affects the last G of the exon (CG/gtgaga to CA/gtgaga) ( Figure 3).…”

“…27 This is in apparent contradiction with linkage studies estimating the contribution of BBS1 locus to be of 32 -56% of BBS families. 25 In this series, the contribution of BBS1 mutations was established for 26% of the families.…”

“…One BBS1 mutation (E549X) found here in a French family has been previously described in patients of PuertoRican origin and may correspond to a recurring hotspot event. 25,27 No mutation in BBS8 The identification of BBS8 has been a major contribution to the understanding of the pathogenesis of the syndrome. However, no mutation could be detected in our series.…”

Cilia, adenomatous polyposis coli and associated diseases

“…The two kinds of genes, BBS1 and BBS10, register as common mutations in most individuals of the BBS syndrome. Most BBS genes encode proteins that participate in the cilia vital activities process, and the functions of the rest of the genes are still unclear (Mykytyn et al, 2003). Most proteins encoded by BBS gene are located in cilia, basal body or centrosome complex.…”