Human homology and candidate genes for the Dominant megacolon locus, a mouse model of Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) is a congenital disorder of the enteric nervous system characterized by the absence of enteric ganglia. Three genes for HSCR have been identified: the RET proto-oncogene, the gene coding for the endothelin B receptor (EDNRB), and the endothelin 3 gene (EDN3). In mice, natural and in vitro-induced mutations affecting the Ret, Ednrb, and Edn3 genes generate a phenotype similar to human HSCR. Another model of HSCR disease is the Dominant megacolon (Dom), a spontaneous mouse mutation for which the target gene has not yet been identified. The Dom mutation has been mapped to the middle-terminal region of mouse chromosome 15, between D15Mit68 and D15Mit2. Using new or known polymorphisms for conserved human/mouse genes, we established the homology between the Dom locus and human chromosome 22q12-q13. Two genes, Smstr3 and Adsl, not previously mapped in the mouse genome, were located on mouse Chromosome 15. Three genes (Smstr3, Lgals1, and Pdgfb) are possible Dom candidates, as they do not recombine with the Dom mutation in a 252 Dom/+ animal backcross.