Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.

Published

Journal Article

Technological advances hold the promise of rapidly catalyzing the discovery of pathogenic variants for genetic disease. However, this possibility is tempered by limitations in interpreting the functional consequences of genetic variation at candidate loci. Here, we present a systematic approach, grounded on physiologically relevant assays, to evaluate the mutational content (125 alleles) of the 14 genes associated with Bardet-Biedl syndrome (BBS). A combination of in vivo assays with subsequent in vitro validation suggests that a significant fraction of BBS-associated mutations have a dominant-negative mode of action. Moreover, we find that a subset of common alleles, previously considered to be benign, are, in fact, detrimental to protein function and can interact with strong rare alleles to modulate disease presentation. These data represent a comprehensive evaluation of genetic load in a multilocus disease. Importantly, superimposition of these results to human genetics data suggests a previously underappreciated complexity in disease architecture that might be shared among diverse clinical phenotypes.

Full Text

Duke Authors

Cited Authors

  • Zaghloul, NA; Liu, Y; Gerdes, JM; Gascue, C; Oh, EC; Leitch, CC; Bromberg, Y; Binkley, J; Leibel, RL; Sidow, A; Badano, JL; Katsanis, N

Published Date

  • June 8, 2010

Published In

Volume / Issue

  • 107 / 23

Start / End Page

  • 10602 - 10607

PubMed ID

  • 20498079

Pubmed Central ID

  • 20498079

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1000219107

Language

  • eng

Conference Location

  • United States