title: 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.
authors: Institut National de la Santé et de la Recherche Médicale U781, 6 Service de Génétique, Hôpital Necker-Enfants-Malades, AP-HP, 75743 Paris, France.
authors: Loïc
authors: L
authors: de Pontual
authors: Norann A
authors: NA
authors: Zaghloul
authors: Sophie
authors: S
authors: Thomas
authors: Erica E
authors: EE
authors: Davis
authors: David M
authors: DM
authors: McGaughey
authors: Hélène
authors: H
authors: Dollfus
authors: Clarisse
authors: C
authors: Baumann
authors: Seneca L
authors: SL
authors: Bessling
authors: Candice
authors: C
authors: Babarit
authors: Anna
authors: A
authors: Pelet
authors: Cecilia
authors: C
authors: Gascue
authors: Philip
authors: P
authors: Beales
authors: Arnold
authors: A
authors: Munnich
authors: Stanislas
authors: S
authors: Lyonnet
authors: Heather
authors: H
authors: Etchevers
authors: Tania
authors: T
authors: Attie-Bitach
authors: Jose L
authors: JL
authors: Badano
authors: Andrew S
authors: AS
authors: McCallion
authors: Nicholas
authors: N
authors: Katsanis
authors: Jeanne
authors: J
authors: Amiel
mesh_terms: D000483:Alleles; D003593:Cytoplasm / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D004843:Epistasis, Genetic; D005192:Family Health; D005260:Female; D005838:Genotype; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013270:Stomach / Q000294:innervation*
chemical_list: C464790:Bbs1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human