HUMAN GFRA1 - CLONING, MAPPING, GENOMIC STRUCTURE, AND EVALUATION AS A CANDIDATE GENE FOR HIRSCHSPRUNG DISEASE SUSCEPTIBILITY

Congenital aganglionic megacolon, commonly known as Hirschsprung disea se (HSCR), is the most frequent cause of congenital bowel obstruction. Germline mutations in the RET receptor tyrosine kinase have been show n to cause HSCR. Knockout mice for RET and for its ligand, glial cell line-derived neurotrophic factor (GDNF), exhibit both complete intesti nal aganglionosis and renal defects. Recently, GDNF and GFRA1 (GDNF fa mily receptor, also known as GDNFR-alpha), its GPI-linked coreceptor, were demonstrated to be components of a functional ligand for RET. Mor eover, GDNF has been implicated in rare cases of HSCR. We have mapped GFRA1 to human chromosome 10q25, isolated human and mouse genomic clon es, determined the gene's intron-exon boundaries, isolated a highly po lymorphic microsatellite marker adjacent to exon 7, and scanned for GF RA1 mutations in a large panel of HSCR patients. No evidence of linkag e was detected in HSCR kindreds, and no sequence variants were found t o be in significant excess in patients. These data suggest that GFRA1' s role in enteric neurogenesis in humans remains to be elucidated and that RET signaling in the gut may take place via alternate pathways, s uch as the recently described GDNF-related molecule neurturin and its GFRA1-like coreceptor, GFRA2. (C) 1998 Academic Press.