title: Detection of a germline mutation at codon 918 of the RET proto-oncogene in French MEN 2B families.
abstract: Multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC) are three dominantly inherited disorders linked to the same disease locus on chromosome 10. Two types of germline mutation of the RET proto-onco-gene, which codes for a transmembrane tyrosine kinase, are associated with MEN 2. Missense mutations at cysteine residues in the extra-cytoplasmic domain are exclusively associated with MEN 2A and FMTC. In MEN 2B patients, a single point mutation at codon 918 has recently been characterized, leading to the replacement of a methionine by a threonine within the RET tyrosine kinase domain. We now report the identification of a mutation at codon 918 in the germline of 16 patients out of 18 unrelated MEN 2B families 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 unique mutation at codon 918 of the RET gene is the most prevalent genetic defect causing MEN 2B, but also that rare MEN 2B cases are associated with different mutations yet to be defined.
authors.affiliation: International Agency for Research on Cancer and EP41 CNRS, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Rossel
authors.forename: I
authors.initials: I
authors.lastname: Schuffenecker
authors.forename: M
authors.initials: M
authors.lastname: Schlumberger
authors.forename: C
authors.initials: C
authors.lastname: Bonnardel
authors.forename: E
authors.initials: E
authors.lastname: Modigliani
authors.forename: P
authors.initials: P
authors.lastname: Gardet
authors.forename: J
authors.initials: J
authors.lastname: Navarro
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: G
authors.initials: G
authors.lastname: Romeo
authors.forename: G
authors.initials: G
authors.lastname: Lenoir
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003062:Codon; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D029721:Drosophila Proteins; D005260:Female; D005602:France / Q000453:epidemiology; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018814:Multiple Endocrine Neoplasia Type 2b / Q000453:epidemiology / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics*
chemical_list: D003062:Codon; D017931:DNA Primers; D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila