title: A RET double mutation in the germline of a kindred with FMTC.
abstract: Activating germline mutations of the RET proto-oncogene are found in more than 90% of families with multiple endocrine neoplasia type 2a (MEN 2a) and familial medullary thyroid carcinoma (FMTC). The majority of patients with these hereditary tumors carry germline mutations that result in the substitution of one of five cysteine residues in exon 10 and 11. Different mutations in exons 13, 14 and 15 affecting non-cysteine residues have also been described but are considered to be rare. We now for the first time report a double mutation of the RET proto-oncogene occurring in the germline of a kindred with FMTC. Both mutations occur within the tyrosine kinase domain in exon 14 and lead to the substitution of valine 804 by methionine and arginine 844 by leucine. Since the double mutated allele cosegregated with the disease and was not identified in 200 unrelated normal probands, we conclude that they represent mutations that predispose the individual to the development of FMTC with a mild phenotype.
authors.affiliation: Department of Surgery, Philipps-University of Marburg, Germany. bartsch@mailer.uni-marburg.de
authors.forename: D K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: C
authors.initials: C
authors.lastname: Hasse
authors.forename: C
authors.initials: C
authors.lastname: Schug
authors.forename: P
authors.initials: P
authors.lastname: Barth
authors.forename: M
authors.initials: M
authors.lastname: Rothmund
authors.forename: W
authors.initials: W
authors.lastname: Höppner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002116:Calcitonin / Q000032:analysis / Q000097:blood; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D009154:Mutation; D010375:Pedigree; 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 / Q000235:genetics* / Q000473:pathology
chemical_list: D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D002116:Calcitonin; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila