Human Molecular Genetics, 2003, Vol. 12, No. 14 1651-1659
DOI: 10.1093/hmg/ddg188
© 2003 Oxford University Press
Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet–Biedl patients with two mutations at a second BBS locus
1Institute of Genetic Medicine, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21287, USA, 2Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6, 3Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK, 4Departments of Molecular and Human Genetics, Ophthalmology, Pediatrics, and Medicine, Baylor College of Medicine, One Baylor Plaza, Houston TX 77030, USA, 5The Clinical Genetics Service, Bolzano General Hospital, Bolzano 39100, Italy and 6Wilmer Eye Institute, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21287, USA
Received March 3, 2003; Accepted May 19, 2003
Bardet–Biedl syndrome (BBS) is a pleiotropic genetic disorder with substantial inter- and intrafamilial variability, that also exhibits remarkable genetic heterogeneity, with seven mapped BBS loci in the human genome. Recent data have demonstrated that BBS may be inherited either as a simple Mendelian recessive or as an oligogenic trait, since mutations at two loci are sometimes required for pathogenesis. This observation suggests that genetic interactions between the different BBS loci may modulate the phenotype, thus contributing to the clinical variability of BBS. We present three families with two mutations in either BBS1 or BBS2, in which some but not all patients carry a third mutation in BBS1, BBS2 or the putative chaperonin BBS6. In each example, the presence of three mutant alleles correlates with a more severe phenotype. For one of the missense alleles, we also demonstrate that the introduction of the mutation in mammalian cells causes a dramatic mislocalization of the protein compared with the wild-type. These data suggest that triallelic mutations are not always necessary for disease manifestation, but might potentiate a phenotype that is caused by two recessive mutations at an independent locus, thus introducing an additional layer of complexity on the genetic modeling of oligogenicity.
* To whom correspondence should be addressed at: Institute of Genetic Medicine, 2-127 Jefferson Street Building, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21287, USA. Tel: +1 4105026660; Fax: +1 4105027544; Email: katsanis{at}jhmi.edu
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