Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.
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.
de Pontual
Loïc
L
Institut National de la Santé et de la Recherche Médicale U781, 6 Service de Génétique, Hôpital Necker-Enfants-Malades, AP-HP, 75743 Paris, France.
Zaghloul
Norann A
NA
Thomas
Sophie
S
Davis
Erica E
EE
McGaughey
David M
DM
Dollfus
Hélène
H
Baumann
Clarisse
C
Bessling
Seneca L
SL
Babarit
Candice
C
Pelet
Anna
A
Gascue
Cecilia
C
Beales
Philip
P
Munnich
Arnold
A
Lyonnet
Stanislas
S
Etchevers
Heather
H
Attie-Bitach
Tania
T
Badano
Jose L
JL
McCallion
Andrew S
AS
Katsanis
Nicholas
N
Amiel
Jeanne
J
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*
C464790:Bbs1 protein, human; D008869:Microtubule-Associated Proteins; D011506:Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human