title: Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.
abstract: Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder 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 difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic 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 previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form 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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110.
authors.forename: K M
authors.initials: KM
authors.lastname: Carlson
authors.forename: S
authors.initials: S
authors.lastname: Dou
authors.forename: D
authors.initials: D
authors.lastname: Chi
authors.forename: N
authors.initials: N
authors.lastname: Scavarda
authors.forename: K
authors.initials: K
authors.lastname: Toshima
authors.forename: C E
authors.initials: CE
authors.lastname: Jackson
authors.forename: S A
authors.initials: SA
authors.lastname: Wells
authors.forename: P J
authors.initials: PJ
authors.lastname: Goodfellow
authors.forename: H
authors.initials: H
authors.lastname: Donis-Keller
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D029721:Drosophila Proteins; D005260:Female; D015894:Genome, Human; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010673:Pheochromocytoma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D029721:Drosophila Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila