Bardet-Biedl syndrome in Newfoundland : molecular genetics of a rare recessive disorder in a small isolated population

Woods, Michael O. (2001) Bardet-Biedl syndrome in Newfoundland : molecular genetics of a rare recessive disorder in a small isolated population. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Bardet-Biedl syndrome (BBS) is characterized by retinal dystrophy, dysmorphicextremities, renal structural abnormalities, obesity, and hypogenitalism in males. This autosomal recessive disorder is genetically heterogenous with four identified loci, BBS1-4 (11q, 16q, 3p and 15q respectively). BBS is a relatively rare disorder, but it is approximately ten times more prevalent in Newfoundland than in northern European populations. -- To investigate the high incidence of BBS in the Newfoundland population, members of 17 BBS families were analyzed by haplotype and linkage analyses. Initially, linkage of five families to BBS1 one each to BBS2 and BBS3 and exclusion of six families from the four known BBS loci was observed. -- A large consanguineous Newfoundland BBS family, excluded from the four known BBS loci, was used to identify a fifth BBS gene locus (BBS5) on 2q31 in a genome-wide scan. However, this gene did not segregate in any other of the five unlinked families. Therefore, another genome scan was implemented on a consanguineous family excluded from the five BBS loci. Evidence of a sixth BBS gene (BBS6) on 20p12 was established and the critical interval narrowed to 2 cM using five other unlinked families. Located within this region is a putative chaperonin gene (MKKS) involved in McKusick-Kaufman syndrome, a disorder with an overlapping phenotype with BBS. When MKKS was screened for mutations in six Newfoundland BBS families, one missense and two frameshift mutations were identified. Thus, MKKS was the first gene identified to cause BBS. Remarkably, one family could be excluded from all six BBS loci, indicating the existence of a seventh BBS gene (BBS7). -- By mutational and/or haplotype and linkage analyses, it was possible to assign 14 of the 17 Newfoundland BBS families to known BBS loci. Six families had mutations in MKKS/BBS6, five families were associated with the BBS1 locus, and one family to each of the BBS2, BBS3 and BBS5 loci. Additionally, one family was excluded from the six known BBS loci. The discovery of MKKS/BBS6 should aid in the ascertainment of other BBS genes and contribute to the basic understanding of the manifestations of BBS.

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