(provided by application): Hirschsprung disease (HSCR) is a complex genetic disorder. The primary clinical feature, aganglionic megacolon, arises as a consequence of anomalies in development of the enteric nervous system and subsequent absence of enteric ganglia. Family members carrying identical gene mutations often exhibit differences in penetrance and length of gut lacking enteric neurons. This variation suggests that - like many human genetic diseases - multiple genes modulate HSCR penetrance and severity. Mouse models of HSCR have successfully identified genes that participate in enteric nervous system pathology. At present five genes are known to contribute to the etiology of human HSCR cases. Four additional genes can contribute to aganglionosis based on phenotypes in the mouse models. Collectively, these genes account for no more than 30 percent of total HSCR cases. The significant challenge remains to identify additional genes and genetic interactions that account for the remaining spectrum of HSCR cases. Four of the known HSCR susceptibility loci are up-regulated in neural crest stem cells (NCSC) indicating that HSCR is a consequence of defects in NCSC function. SoxW is highly expressed in NCSC and is deficient in a subset of HSCR cases. Sox10??m mice recapitulate aganglionosis and other extra-intestinal autonomic deficits observed in HSCR patients. Our prior studies of SoxW have established that genetic background impacts severity of intestinal aganglionosis. We have successfully localized five modifier loci of Sox1(P?m that affect penetrance and severity of aganglionosis. Two of the genes that underlie these modifier loci have been definitively identified. The goal of the proposed studies is gain a more complete understanding of the genetic underpinnings of aganglionosis by identifying additional genes and the gene interactions that impact this disease. The experimental strategy will increase our understanding of pathways essential for enteric development and pathogenesis of gastrointestinal dysmotility syndromes.
Aim 1 will use genome-wide analysis of a large F2 cohort and an extended FT backcross pedigree of Sox10??m mice to identify refined intervals of aganglionosis modifiers and define genetic interactions that impact severity and penetrance of this phenotype.
Aim 2 will define Sox10??m phenotype variation across multiple inbred strains and identify shared haplotypes that alter aganglionosis by quantifying extent of enteric deficits in FT progeny derived from Sox10?om congenic lines. Genome-wide haplotype association will identify genetic intervals of previously undetected Sox70 modifiers shared between strains.
Aim 3 will establish mechanisms of SoxW modifier interaction by transcriptional profiling of enteric NCSC in SoxWP?m congenic lines during critical stages of neural crest migration within the developing gastrointestinal tract. Our analysis will reveal the complex genetic architecture of HSCR, establish how signaling pathways in NCSC interact to produce aganglionosis at the organismal level, and identify potential therapeutic targets in Gl dysmotility syndromes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Karp, Robert W
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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