Dissection of epistasis in oligogenic Bardet-Biedl syndrome

Nature. 2006 Jan 19;439(7074):326-30. doi: 10.1038/nature04370. Epub 2005 Dec 4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Alternative Splicing / genetics
  • Animals
  • Bardet-Biedl Syndrome / genetics*
  • Base Sequence
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Epistasis, Genetic*
  • Exons / genetics
  • Female
  • Heterozygote
  • Humans
  • Linkage Disequilibrium
  • Male
  • Microtubule-Associated Proteins
  • Multifactorial Inheritance / genetics*
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Protein Binding
  • Proteins / genetics
  • Proteins / metabolism
  • RNA Splice Sites / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics

Substances

  • Bbs1 protein, human
  • CCDC28B protein, human
  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Proteins
  • RNA Splice Sites
  • RNA, Messenger