Dissection of epistasis in oligogenic Bardet-Biedl syndrome.


Journal Article

Epistatic interactions have an important role in phenotypic variability, yet the genetic dissection of such phenomena remains challenging. Here we report the identification of a novel locus, MGC1203, that contributes epistatic alleles to Bardet-Biedl syndrome (BBS), a pleiotropic, oligogenic disorder. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of two independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. Further analyses showed that the 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants. Our data demonstrate how the combined use of biochemical, genetic and in vivo tools can facilitate the dissection of epistatic phenomena, and enhance our appreciation of the genetic basis of phenotypic variability.

Full Text

Cited Authors

  • Badano, JL; Leitch, CC; Ansley, SJ; May-Simera, H; Lawson, S; Lewis, RA; Beales, PL; Dietz, HC; Fisher, S; Katsanis, N

Published Date

  • January 2006

Published In

Volume / Issue

  • 439 / 7074

Start / End Page

  • 326 - 330

PubMed ID

  • 16327777

Pubmed Central ID

  • 16327777

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature04370


  • eng