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Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13921-6. doi: 10.1073/pnas.0901219106. Epub 2009 Jul 31.

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

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Institut National de la Santé et de la Recherche Médicale U781, 6 Service de Génétique, Hôpital Necker-Enfants-Malades, AP-HP, 75743 Paris, France.


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.

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