The glial-cell-line-derived neurotrophic factor (GDNF) family receptors alpha 
(GFRalpha) are cell surface bound glycoproteins that mediate interactions of the 
GDNF ligand family with the RET receptor. These interactions are crucial to the 
development of the kidney and some peripheral nerve lineages. In humans, 
mutations of RET or RET ligands are associated with the congenital abnormality 
Hirschsprung disease (HSCR) in which nerves and ganglia of the hind gut are 
absent. As the GFRalpha family are required for normal activation of the RET 
receptor, they are also candidates for a role in HSCR. The GFRA2 gene, which is 
required for the development of the myenteric nerve plexus, is an excellent 
candidate gene for HSCR. In this study, we cloned the human GFRA2 locus, 
characterized the gene structure, and compared it with other GFRA family 
members. We further investigated the GFRA2 gene for mutations in a panel of HSCR 
patients. GFRA2 has nine coding exons that are similar in size and organization 
to those of other GFRA family genes. We identified six sequence variants of 
GFRA2, four of which did not affect the amino acid sequence of the GFRalpha-2 
protein. Two further changes that resulted in amino acid substitutions were 
found in exon 9 and were predicted to lie in the amino acid sequence encoding 
the glycosylphosphatidylinositol-linkage signal of GFRalpha-2. There was no 
difference in frequency of any of the sequence variants between control and HSCR 
populations. Our data indicate that members of the GFRA gene family are closely 
related in intron/exon structure and in sequence. We have not detected any 
correlation between sequence variants of GFRA2 and the HSCR phenotype.