MUTATIONS OF THE RET PROTOONCOGENE IN HIR SCHSPRUNGS-DISEASE

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live b irths) resulting in intestinal obstruction in neonates and megacolon i n infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletel y penetrant dominant inheritance in familial HSCR. Recently, a gene fo r HSCR has been mapped to chromosome 10q11.2. No recombination was obs erved between the disease locus and the locus for the RET proto-oncoge ne, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report on nonsense and missense mutations i n the extracellular domain of the RET protein (exons 2, 3, 5 and 6) in 6 unrelated probands and show that the mutant genotypes segregate wit h the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ- line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.