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

Loïc De Pontual, Norann A. Zaghloul, Sophie Thomas, Erica Ellen Davis, David M. Mcgaughey, Hélène Dollfus, Clarisse Baumann, Seneca L. Bessling, Candice Babarit, Anna Pelet, Cecilia Gascue, Philip Beales, Arnold Munnich, Stanislas Lyonnet, Heather Etchevers, Tania Attie-Bitach, Jose L. Badano, Andrew S. McCallion, Elias Nicholas Katsanis*, Jeanne Amiel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)13921-13926
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number33
StatePublished - Aug 18 2009


  • Bardet-Biedl
  • Genetic interaction
  • Neural crest cells
  • Zebrafish

ASJC Scopus subject areas

  • General


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