International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 179 - A GENOME-WIDE APPROACH FOR IDENTIFICATION OF MODIFIER GENES OF HIRSCHSPRUNG DISEASE IN THE SOX10DOM MOUSE MODEL

Owens S
Vanderbilt University

Co-Authors: Chandler R, Southard-Smith M
Institutions: Vanderbilt University

Hirschsprung disease (HSCR) is caused by abnormal development of the neural crest cells that comprise the enteric nervous system, resulting in an absence or reduction of enteric ganglia in a variable portion of the distal gastrointestinal tract.

Dominant megacolon (Sox10Dom) mice model the aganglionic megacolon seen in HSCR and SOX10 mutations have been identified in a subset of HSCR patients. Sox10Dom heterozygote mice on a mixed genetic (B6C3F1) background mimic the variable severity of aganglionosis in HSCR patients. Analysis of B6.Sox10Dom and C3Fe.Sox10Dom congenic lines demonstrates that this variation is influenced by genetic background.

To establish linkage to modifier genes that modulate the severity of aganglionosis in Sox10Dom mice we initiated a genome-wide scan. Intestinal aganglionosis was quantified by whole-mount acetylcholinesterase (AChE) histochemistry on gastrointestinal tracts from postnatal day 7-10 backcross (n=204) and intercross (n=1092) progeny. Mice from the extremes of the phenotype distribution are being genotyped by fluorescence polarization methods to distinguish 150 SNP markers at 10 cM spacing throughout the genome. Initial analysis of aganglionosis in B6N15xC3Fe.Sox10Dom indicates F1 mice resemble the C3Fe.Sox10Dom/+ phenotype, suggesting that C3Fe alleles exert dominant effects. Application of the Castle-Wright equation to backcross progeny suggests a minimum estimate of 0.4 genes contributing to the difference in severity of aganglionosis. Preliminary results of linkage analysis will be presented.


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