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

Loïc De Pontual, Norann A. Zaghloul, Sophie Thomas, Erica E. 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, Nicholas Katsanis, Jeanne Amiel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)13921-13926
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number33
DOIs
StatePublished - Aug 18 2009

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Hirschsprung Disease
Mutation
Biological Phenomena
Regulator Genes
Genes
Alleles

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. / De Pontual, Loïc; Zaghloul, Norann A.; Thomas, Sophie; Davis, Erica E.; Mcgaughey, David M.; Dollfus, Hélène; Baumann, Clarisse; Bessling, Seneca L.; Babarit, Candice; Pelet, Anna; Gascue, Cecilia; Beales, Philip; Munnich, Arnold; Lyonnet, Stanislas; Etchevers, Heather; Attie-Bitach, Tania; Badano, Jose L.; McCallion, Andrew S; Katsanis, Nicholas; Amiel, Jeanne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 33, 18.08.2009, p. 13921-13926.

Research output: Contribution to journalArticle

De Pontual, L, Zaghloul, NA, Thomas, S, Davis, EE, Mcgaughey, DM, Dollfus, H, Baumann, C, Bessling, SL, Babarit, C, Pelet, A, Gascue, C, Beales, P, Munnich, A, Lyonnet, S, Etchevers, H, Attie-Bitach, T, Badano, JL, McCallion, AS, Katsanis, N & Amiel, J 2009, '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, vol. 106, no. 33, pp. 13921-13926. https://doi.org/10.1073/pnas.0901219106
De Pontual, Loïc ; Zaghloul, Norann A. ; Thomas, Sophie ; Davis, Erica E. ; Mcgaughey, David M. ; Dollfus, Hélène ; Baumann, Clarisse ; Bessling, Seneca L. ; Babarit, Candice ; Pelet, Anna ; Gascue, Cecilia ; Beales, Philip ; Munnich, Arnold ; Lyonnet, Stanislas ; Etchevers, Heather ; Attie-Bitach, Tania ; Badano, Jose L. ; McCallion, Andrew S ; Katsanis, Nicholas ; Amiel, Jeanne. / Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 33. pp. 13921-13926.
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