The study focused on genes of potential relevance to enteric nerve (ENS) maturation and Hirschsprung's disease or megacolon, based on the literature (GFRA1, NKX2-1, KIF26A, TPM3, ACTG2, SCN10A, and C17orf107 [CHRNE]) and other genetic variants that co-segregated with megacolon in the six affected family members.
In normal infants and normoganglionic colon of patients with HSCR, the expression of GFRA1 was restricted to the glial cells and neurones of the ganglion plexuses.
Glial cell line-derived neurotrophic factor family receptors are abnormally expressed in aganglionic bowel of a subpopulation of patients with Hirschsprung's disease.
Targeted mutagenesis in transgenic mice has shown that Ret, GFR alpha 1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease.
We have mapped GFRA1 to human chromosome 10q25, isolated human and mouse genomic clones, determined the gene's intron-exon boundaries, isolated a highly polymorphic microsatellite marker adjacent to exon 7, and scanned for GFRA1 mutations in a large panel of HSCR patients.