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

Loïc de Pontual (1) , Norann A Zaghloul (2) , Sophie Thomas (1) , Erica E Davis (2) , David M Mcgaughey (2) , Hélène Dollfus (3) , Clarisse Baumann (4) , Seneca L Bessling (2) , Candice Babarit (1) , Anna Pelet (1) , Cecilia Gascue (5) , Philip Beales (6) , Arnold Munnich (1, 6) , Stanislas Lyonnet (1, 6) , Heather C. Etchevers (1) , Tania Attie-Bitach (1) , Jose L Badano (5) , Andrew S Mccallion (2, 7) , Nicholas Katsanis (2, 8, 9) , Jeanne Amiel (1, 6)

1 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
2 McKusick-Nathans Institute of Genetic Medicine
3 Service de génétique médicale
4 Unité fonctionnelle de génétique clinique
5 Institut Pasteur de Montevideo
6 Molecular Medicine Unit
7 Department of Molecular and Comparative Pathology
8 Center for Human Disease Modeling
9 Department of Molecular Biology and Genetics and Wilmer Eye Institute

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.

Domains: Human genetics

Loïc de Pontual, Norann A Zaghloul, Sophie Thomas, Erica E Davis, David M Mcgaughey, et al.. Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.. Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 (33), pp.13921-6. ⟨10.1073/pnas.0901219106⟩. ⟨pasteur-00604838⟩