Hirschsprung disease (HSCR [MIM 142623]) is a developmental disorder resulting from the arrest of the craniocaudal migration of enteric neurons from the neural crest along gastrointestinal segments of variable length (Behrman 1992). The involvement of the Ret proto-oncogene and the endothelin-B receptor-mediated signaling pathways in the migration and differentiation of enteric ganglion cells has been demonstrated in both humans and mice.

Heterozygous, incompletely penetrant point mutations and deletions of the RET proto-oncogene have been described in sporadic and familial cases of HSCR (Edery et al. 1994; Romeo et al. 1994; Angrist et al. 1995). In addition, homozygous RET-targeted disruption in mice results in megacolon with renal abnormalities (Schuchardt et al. 1994). This phenotype is reminiscent of the knockout for GDNF, encoding for the glial cell-line–derived neurotrophic growth factor (Moore et al. 1996; Pichel et al. 1996; Sanchez et al. 1996), a protein that has been demonstrated to bind specifically and to activate Ret with a glycophosphatidylinositol (GPI)-anchored protein, the GDNF receptor-a (GFRA1)(Jing et al. 1996; Treanor et al. 1996). Although no nucleotide changes have been found at the GFRA1 locus (Angrist et al. 1998; Myers et al. 1998), rare heterozygous mutations of the GDNF gene, in some cases in combination