Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. - RIIP - Réseau International des Instituts Pasteur Access content directly
Journal Articles Proceedings of the National Academy of Sciences of the United States of America Year : 2009

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

Abstract

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
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Dates and versions

pasteur-00604838 , version 1 (29-06-2011)

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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⟩
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