SINGLE MISSENSE MUTATION IN THE TYROSINE KINASE CATALYTIC DOMAIN OF THE RET PROTOONCOGENE IS ASSOCIATED WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndro me characterized by medullary thyroid carcinoma (MTC), pheochromocytom as, mucosal neuromas, ganglioneuromas of the intestinal tract, and ske letal and ophthalmic abnormalities. It appears both as an inherited di sorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence diffe rence was not observed in 93 unaffected individuals, including the nor mal parents of 14 de novo MEN 2B patients. The mutation (ATG --> ACG) results in the replacement of methionine with threonine within the cat alytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previ ously have been associated with two other disorders [MEN 2A and famili al MTC (FMTC)] in which MTC is observed. MEN 2B represents the third f orm of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.