Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.


Journal Article

Hirschsprung disease (HSCR) is a common, multigenic neurocristopathy characterized by incomplete innervation along a variable length of the gut. The pivotal gene in isolated HSCR cases, either sporadic or familial, is RET. HSCR also presents in various syndromes, including Shah-Waardenburg syndrome (WS), Down (DS), and Bardet-Biedl (BBS). Here, we report 3 families with BBS and HSCR with concomitant mutations in BBS genes and regulatory RET elements, whose functionality is tested in physiologically relevant assays. Our data suggest that BBS mutations can potentiate HSCR predisposing RET alleles, which by themselves are insufficient to cause disease. We also demonstrate that these genes interact genetically in vivo to modulate gut innervation, and that this interaction likely occurs through complementary, yet independent, pathways that converge on the same biological process.

Full Text

Cited Authors

  • de Pontual, L; Zaghloul, NA; Thomas, S; Davis, EE; McGaughey, DM; Dollfus, H; Baumann, C; Bessling, SL; Babarit, C; Pelet, A; Gascue, C; Beales, P; Munnich, A; Lyonnet, S; Etchevers, H; Attie-Bitach, T; Badano, JL; McCallion, AS; Katsanis, N; Amiel, J

Published Date

  • August 18, 2009

Published In

Volume / Issue

  • 106 / 33

Start / End Page

  • 13921 - 13926

PubMed ID

  • 19666486

Pubmed Central ID

  • 19666486

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.0901219106


  • eng

Conference Location

  • United States