Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Beidl patients with two mutations at a second BBS locus

Jose L. Bandano, Jun Chul Kim, Bethan E. Hoskins, Richard Alan Lewis, Stephen J. Ansley, David J. Cutler, Claudio Castellan, Philip L. Beales, Michel R. Leroux, Elias Nicholas Katsanis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1651-1659
Number of pages9
JournalHuman molecular genetics
Volume12
Issue number14
DOIs
StatePublished - Jul 15 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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