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National Academy of Sciences, Proceedings of the National Academy of Sciences, 33(106), p. 13921-13926, 2009

DOI: 10.1073/pnas.0901219106

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

Journal article published in 2009 by Loïc de Pontual, Norann A. Zaghloul, Sophie Thomas, Erica Ee Davis, David M. Mcgaughey ORCID, Hélène Dollfus, Clarisse Baumann, Seneca L. Bessling, Candice Babarit, Anna Pelet, Cecilia Gascue, Philip Beales, Arnold Munnich, Stanislas Lyonnet, Heather Etchevers and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.