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

• Published in: Human molecular genetics 1996-12, Vol.5 (12), p.2023-2026
• Main Authors: Ivanchuk, Stacey M., Myers, Shirley M., Eng, Charis, Mulligan, Lois M.
• Format: Article
• Language: English
• Subjects: Drosophila Proteins; Glial Cell Line-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor Receptors; Hirschsprung Disease - genetics; Hirschsprung Disease - metabolism; Humans; Ligands; Mutation; Nerve Growth Factors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases - metabolism
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/5.12.2023

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.