Further support for digenic inheritance in Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterised by the primary features of obesity, retinal dystrophy, polydactyly, renal malformations, mental retardation, and hypogenitalism. Patients with BBS also have an increased risk for developing diabetes mellitus, hypertension, and congenital heart disease. Seven loci have been mapped with evidence of at least one additional locus1: 11q13 ( BBS1 ),2 16q21 ( BBS2 ),3 3p13 p12 ( BBS3 ),4 15q22.3q23 ( BBS4 ),5 2q31 ( BBS5 ),6 20p12 ( BBS6 ),7 and 4q27 ( BBS7 ).8 Five genes have been cloned so far: BBS1 ,9 BBS2 ,10 BBS4 ,11 MKKS ( BBS6 ),7,12,13 and BBS7. 8 The function of these genes and the disease mechanism remain unclear. Whereas the BBS6 protein has similarity to a bacterial chaperonin, the other BBS proteins have no significant similarity to archebacterial chaperonins or other known proteins. Before the BBS1 gene had been cloned, a report had suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS, a so called triallelic inheritance.14 Also, many cases with only one mutant allele suggested an unusual mechanism of inheritance.15 In this study, we have analysed whether there is evidence for multiallelic inheritance in patients with BBS by sequencing the complete coding region and exon-intron boundaries of four cloned BBS genes ( BBS1, BBS2, BBS4, and MKKS ) which represent most of the mapped loci. The study was completed before the gene BBS7 was published and thus it is not included in the analysis. As BBS7 seems to be a minor locus, this will have little effect on the outcome. Twenty-one unrelated European patients with the clinical diagnosis of BBS were used in the study. The diagnosis was based on the …