Hirschsprung disease (HSCR) is a complex disorder characterised by aganglia of 
distal gastrointestinal tracts. The highest proportion of both familial and 
sporadic cases is due to mutations of the RET proto-oncogene. Five germline 
mutations in the glial cell-line-derived neurotrophic factor (GDNF) gene, one of 
the RET ligands, have been detected in HSCR patients. Pedigrees analysis and the 
observed association between these GDNF alterations and RET variants in the same 
patients raised the question of whether the GDNF gene plays any 
causative/predisposing role in HSCR pathogenesis. In the present work, we have 
studied the ability of GDNF proteins, each bearing one of the reported 
mutations, to activate RET by performing a functional test in cultured 
neuroblastoma cells. Consistently with the lack of genotype/phenotype 
correlation in human subjects, our results indicate absence of detectable 
alterations of mutant GDNF induced RET activation.