Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease.
Proc Natl Acad Sci U S A
; 106(33): 13921-6, 2009 Aug 18.
Article
in En
| MEDLINE
| ID: mdl-19666486
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stomach
/
Proteins
/
Epistasis, Genetic
/
Proto-Oncogene Proteins c-ret
/
Hirschsprung Disease
/
Mutation
Type of study:
Etiology_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2009
Document type:
Article
Affiliation country:
France