International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 49 - MODIFIERS OF AGANGLIONIC MEGACOLON IDENTIFIED BY EVALUATION OF CANDIDATE GENES IN THE SOX10DOM HIRSCHSPRUNG DISEASE MODEL

Cantrell VA, Owens SE, Chandler RL, Bradley KM, Smith JR, Southard-Smith EM

Vanderbilt University, Nashville, United States

Abnormalities in proliferation, migration, or survival of enteric neural crest (NC) can lead to aganglionosis in a variable portion of the distal intestine, Hirschsprung disease (HSCR).  Cumulative evidence suggests HSCR is the consequence of multiple gene interactions that modulate the ability of enteric NC cells to populate the developing gut. 

One of the essential genes for enteric ganglia development is the NC transcription factor Sox10Sox10Dom mice on a mixed genetic background exhibit variable penetrance and expressivity of aganglionic megacolon reminiscent of human HSCR families.  We have established congenic lines of Sox10Dom mice that fix this allele on distinct genetic backgrounds, C57BL/6J and C3HeB/FeJ.  Differences in survival and degree of aganglionosis between Sox10Dom animals in these lines demonstrate that aganglionosis is influenced by heritable factors.

To identify genes responsible for variation in aganglionic megacolon we have collected mice from the phenotypic extremes of an extended B6C3F F1.Sox10Dom pedigree.  Animals were stratified based either on survival or on extent of gastrointestinal tract affected as determined by acetylcholinesterase histochemistry.  Genotyping was performed with genetic markers closely flanking known HSCR susceptibility loci and genes that affect NC development to test for associations with severity of aganglionosis.  Our single locus association analysis indicates several candidate loci interact with Sox10Dom to influence the severity of aganglionosis in this HSCR model.  Crosses between mutants in the genes that exhibit significant association and Sox10Dom mice support the significance of these gene interactions and illustrate their impact on aganglionosis in double heterozygous progeny. 

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