Abstract
Multiple endocrine neoplasia type 2A (MEN2A), 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-oncogene, 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.
Similar content being viewed by others
References
Carlson KM, Dou S, Chi D, Scavarda N, Toshima K, Jackson CE, Wells Jr, SA, Goodfellow PJ, Donis-Keller H (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 91:1579–1583
Ceccherini I, Bocciardi R, Luo Y, Pasini B, Hofstra R, Takahashi M, Romeo G (1993) Exon structure and flanking intronic sequences of the human RET proto-oncogene. Biochem Biophys Res Commun 196:1288–1295
Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P, Wells Jr, SA (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851–856
Eng CE, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheumann GFW, Jackson CE, Tunnacliffe A, Ponder BAJ (1994) Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3:237–241
Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener J, Ploos van Amstel HK, Romeo G, Lips C, Buys CHCM (1994) A mutation in the RET protooncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367:375–376
Laird PW, Zijderveld A, Linders K, Rudnicki MA, Jaenisch R, Berns A (1991) Simplified mammalian DNA isolation procedure. Nucleic Acids Res 19:4293
Lairmore TC, Howe JR, Korte JA, Dilley WG, Aine L, Aine E, Wells Jr, SA, Donis-Keller H (1991) Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A. Genomics 9:181–192
Landvaster RM, Mathew CGP, Smith BA, Marcus EM, TeMeerman GJ, Lips CJM, Geerdink RA, Nakamura Y, Ponder BAJ, Buys CHCM (1989) Development of multiple endocrine neoplasia type 2A does not involve substantial deletions of chromosome 10. Genomics 4:246–250
Mathew CGP, Chin KS, Easton DF, Thorpe K, Carter C, Liou GI, Fong SL, Bridges CDB, Haak H, Nieuwenhuijzen Kruseman AC, Schifter S, Hansen HH, Telenius H, Telenius-Berg M, Ponder BAJ (1987) A linked genetic marker for multiple endocrine neoplasia type 2A on chromosome 10. Nature 328: 527–528
Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Telenius H, Tunnacliffe A, Ponder BAJ (1993a) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460
Mulligan LM, Gardner E, Smith B, Mathew CGP, Ponder BAJ (1993b) Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2. Genes Chrom Cancer 6: 166–177
Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JBJ, Gardner E, Ponder MA, Frilling A, Jackson CE, Lehnert H, Neumann HPH, Thibodeau SN, Ponder BAJ (1994) Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genet 6:70–74
Narod SA, Sobol H, Nakamura Y, Calmettes C, Baulieu JL, Bigorgne JC, Chabrier G, Couette J, De Gennes JL, Duprey J, Gardet P, Guillausseau PJ, Guilloteau D, Houdent C, Lefebvre J, Modigliani E, Parmentier C, Pugeat M, Siame C, Tourniaire J, Vandroux JC, Vinot JM, Lenoir GM (1989) Linkage analysis of hereditary thyroid carcinoma with and without pheochromocytoma. Hum Genet 83:353–358
Nelkin BD, Nakamura Y, White RW, deBustros AC, Herman J, Wells SA, Baylin SB (1989) Low incidence of loss of chromosome 10 in sporadic and hereditary human medullary thyroid carcinoma. Cancer Res 49:4114–4119
Norum RA, Lafreniere RG, O'Neal LW, Nikolai TF, Delaney JP, Sisson JC, Sobol H, Lenoir GM, Ponder BAJ, Willard HF, Jackson CE (1990) Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A. Genomics 8:313–317
Pachnis V, Mankoo B, Constantini F (1993) Expression of the cret proto-oncogene during mouse embryogenesis. Development 119:1005–1017
Santoro M, Rosati R, Grieco M, Berlingieri MT, Luca-Colucci D'Amato G, De Franciscis V, Fusco A (1990) The RET protooncogene is consistently expressed in human pheochromocytomas and thyroid medullary carcinomas. Oncogene 5: 1595–1598
Schimke RN (1984) Genetic aspects of multiple endocrine neoplasia. Annu Rev Med 35:25–31
Schneider R (1992) The human protooncogene RET: a communicative cadherin? Trends Biochem Sci 17:468–469
Simpson NE, Kidd KK, Goodfellow PJ, McDermid H, Myers S, Kidd JR, Jackson CE, Duncan AMV, Farrer LA, Brasch K, Castiglione C, Genel M, Gertner J, Greenberg CR, Gusella JF, Holden JJA, White R (1987) Assignment of multiple endocrine neoplasia type 2A to chromosome 10 by linkage. Nature 328: 528–530
Takahashi M, Buma Y, Iwamoto T, Inaguma Y, Ikeda H, Hiai H (1988) Cloning and expression of the RET proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3:571–578
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rossel, M., Bonnardel, C., Lenoir, G. et al. Detection of a germline mutation at codon 918 of the RET proto-oncogene in French MEN 2B families. Hum Genet 95, 403–406 (1995). https://doi.org/10.1007/BF00208964
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00208964