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Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of enteric nervous plexuses in hind gut. Ten to forty percent of HSCR patients carry a dominant loss-of-function mutation in the gene encoding the receptor tyrosine kinase RET, a receptor for glial cell line-derived neurotrophic factor (GDNF). Although several mutations have also been found in the GDNF gene of HSCR patients, their impact on GDNF function is unknown. In this study, we have characterized the effect of these mutations on the ability of GDNF to bind and activate its receptors. Although none of the four mutations analyzed appeared to affect the ability of GDNF to activate RET, two of them resulted in a significant reduction in the binding affinity of GDNF for the binding subunit of the receptor complex, GFR(alpha)1. Our results indicate that, although none of the GDNF mutations identified so far in HSCR patients are per se likely to result in HSCR, two of these mutations (i.e. D150N and I211M) may, in conjunction with other genetic lesions, contribute to the pathogenesis of this disease.

Functional characterization of mutations in the GDNF gene of patients with Hirschsprung disease