De Novo Mutation of GDNF, Ligand for the RET/GDNFR-α Receptor Complex, in Hirschsprung Disease

Author： Ivanchuk Stacey M. Myers Shirley M. Eng Charis Mulligan Lois M.

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.5, Iss.12, 1996-12, pp. : 2023-2026

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Abstract

Hirschsprung disease (HSCR) is a common congenital abnormality characterized by absence of the enteric ganglia in the hind gut. In 10–40% of HSCR cases, mutations of the RET receptor tyrosine kinase have been found. The recent identification of a multimeric RET ligand/receptor complex suggested that mutations of genes encoding other components of this complex might also occur in HSCR. To investigate this role, we examined the gene for glial cell line-derived neurotrophic factor (GDNF), the circulating ligand of the RET receptor complex, for mutations in a panel of sporadic and familial HSCR. We identified GDNF sequence variants in 2/36 HSCR patients. The first of these was a conservative change which did not affect the GDNF protein sequence. The second variant was a De Novo missense mutation in a family with no history of HSCR and without mutation of the RET gene. Thus, our data are consistent with a causative role for GDNF mutations in some HSCR cases.