DETECTION OF A GERMLINE MUTATION AT CODON-918 OF THE RET PROTOONCOGENE IN FRENCH MEN 2B FAMILIES

Multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and f amilial medullary thyroid carcinoma (FMTC) are three dominantly inheri ted disorders linked to the same disease locus on chromosome 10. Two t ypes of germline mutation of the RET proto-oncogene, which codes for a transmembrane tyrosine;kinase, are associated with MEN 2. Missense mu tations at cysteine residues in the extra-cytoplasmic domain are exclu sively associated with MEN 2A and FMTC. In MEN 2B patients, a single p oint mutation at codon 918 has recently been characterized, leading to the replacement of a methionine by a threonine within the RET tyrosin e kinase domain. We now report the identification of a mutation at cod on 918 in the germline of 16 patients out of 18 unrelated MEN 2B famil ies analyzed. In these families we have been able to demonstrate that, in five cases, the mutation arose de novo, and that, in one kindred, it was coinherited with the disease. These results indicate that a uni que mutation at codon 918 of the RET gene is the most prevalent geneti c defect causing MEN 2B, but also that rare MEN 2B cases are associate d with different mutations yet to be defined.