title: Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.
abstract: Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
authors.affiliation: Division of Human Molecular Genetics, Washington University School of Medicine, St Louis, MO 63110.
authors.forename: H
authors.initials: H
authors.lastname: Donis-Keller
authors.forename: S
authors.initials: S
authors.lastname: Dou
authors.forename: D
authors.initials: D
authors.lastname: Chi
authors.forename: K M
authors.initials: KM
authors.lastname: Carlson
authors.forename: K
authors.initials: K
authors.lastname: Toshima
authors.forename: T C
authors.initials: TC
authors.lastname: Lairmore
authors.forename: J R
authors.initials: JR
authors.lastname: Howe
authors.forename: J F
authors.initials: JF
authors.lastname: Moley
authors.forename: P
authors.initials: P
authors.lastname: Goodfellow
authors.forename: S A
authors.initials: SA
authors.lastname: Wells
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009377:Multiple Endocrine Neoplasia / Q000201:enzymology / Q000235:genetics*; D009690:Nucleic Acid Conformation; D015345:Oligonucleotide Probes; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C000715470:MAS1 protein, human; D015345:Oligonucleotide Probes; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila