Single Missense Mutation in the Tyrosine Kinase Catalytic Domain of the RET Protooncogene is Associated with Multiple Endocrine Neoplasia Type 2B

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 4; pp. 1579 - 1583
• Main Authors: Carlson, Katrin M., Dou, Shenshen, Chi, David, Scavarda, Nancy, Toshima, Koji, Jackson, Charles E., Wells, Samuel A., Goodfellow, Paul J., Donis-Keller, Helen
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.02.1994; National Acad Sciences; National Academy of Sciences
• Subjects: Alleles; Amino Acid Sequence; Amino acids; Base Sequence; Biological and medical sciences; Codons; Drosophila Proteins; Endocrine system; Endocrinopathies; Exons; Female; General aspects. Associated endocrine diseases. Endocrine paraneoplasic syndromes; Genetic mutation; Genome, Human; Genomics; Humans; Male; man; Medical sciences; missense mutant; Models, Genetic; Molecular Sequence Data; multiple endocrine neoplasia; Multiple Endocrine Neoplasia - genetics; Multiple endocrine neoplasia type 2a; Multiple endocrine neoplasia type 2b; Mutation; nucleotide sequence; oncogenes; Pedigree; Pheochromocytoma - genetics; Polymerase Chain Reaction; protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-ret; Receptor Protein-Tyrosine Kinases - genetics; Receptors; ret gene; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Tumors; type 2B; Endocrinopathy; Human; Enzyme; Transferases; Malignant tumor; Multiple endocrine neoplasia type II; Genetic disease; Missense mutation; Etiology; Genetics; Localization; Protein-tyrosine kinase; Protooncogene
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.4.1579

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.