Exp Clin Endocrinol Diabetes 2000; Vol. 108(2): 128-132
DOI: 10.1055/s-2000-5806
Articles

© Johann Ambrosius Barth

A RET double mutation in the germline of a kindred with FMTC

D. K. Bartsch 1 , C. Hasse 1 , C. Schug 1 , P. Barth 2 , M. Rothmund 1 , W. Höppner 3
  • 1 Department of Surgery, Philipps-University of Marburg, Marburg, Germany
  • 2 Department of Pathology, Philipps-University of Marburg, Marburg, Germany
  • 3 Institute for Hormone and Fertility Research, University of Hamburg, Hamburg, Germany
Further Information

Publication History

Publication Date:
31 December 2000 (online)

Summary:

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 heriditary 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 occuring 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.

References

  • 1 Asai N, Iwashita T, Matsuyama M, Takahashi M. Mechanism of activation of the RET proto-oncogene by multiple endocrine neoplasia type 2a mutations.  Mol Cell Biol. 15 1613-1619 1995; 
  • 2 Berndt N, Reuter M, Saller B, Frank-Raue K, Groth P, Grubendorf M, Raue F, Ritter M M, Höppner W. A new hot spot for mutations in the RET proto-oncogene causing familial medullary thyroid carcinoma and MEN type 2a.  J Clin Endocrinol Metabol. 83 770-774 1998; 
  • 3 Bolino A, Schuffenecker I, Luo Y, Seri M, Silengo M, Tocco T, Chabrier G, Houdent C, Murat A, Schlumberger M, Tourniaire J, Lenoir G, Romeo G. RET mutations in exons 13 and 14 of FMTC patients.  Oncogene. 10 2415-2419 1995; 
  • 4 Carlson K M, Dou S, Chi D, Scarvada N, Toshima K, Jackson C E, Wells S A, Goodfellow P J, Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of RET proto-oncogene is associated with multiple endocrine neoplasia type 2B.  Proc Natl Acad Sci USA. 91 1579-1583 1994; 
  • 5 Donis-Keller H, Dou S, Chi D, Carlson K M, Toshima K, Lairymore T C, Howe J R, Moley J F, Goodfellow P J, Wells S A. Mutations in the RET proto-oncogene are associated with MEN2a and FMTC.  Hum Mol Genet. 2 851-856 1993; 
  • 6 Eng C, Smith D P, Mulligan L M, Nagai M A, Healey C S, Ponder M A, Gardner E, Scheumann G FW, Jackson C E, Tunnacliffe A, Ponder B AJ. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2 and related sporadic tumours.  Hum Mol Genet. 3 237-241 1994; 
  • 7 Eng C, Smith D P, Mulligan L M, Healey C S, Zvelebil M J, Stonehouse T J, Ponder M A, Jackson C E, Waterfield M D, Ponder B AJ. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC.  Oncogene. 10 509-513 1995; 
  • 8 Fink M, Weinhusel A, Niederle B, Haas O A. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene.  Int J Cancer. 69 312-316 1996; 
  • 9 Frank-Raue K, Höppner W, Frillig A, Kotzerke J, Dralle H, Haase R, Mann K, Seif F, Kirchner R, Rendl J, Deckart H, Ritter M, Hampel R, Klempa J, Scholz G, Raue F. the German Medullary Thyroid Carcinoma Study Group . Mutations of the RET proto-oncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype.  J Clin Endocrinol Metab. 81 1780-1783 1996; 
  • 10 Goodfellow P J, Wells S A. RET gene and its implications for cancer.  J Natl Cancer Inst. 87 1515-1523 1995; 
  • 11 Höppner W, Ritter M M. A duplication of 12bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of MEN type 2a.  Hum Mol Genet. 6 587-590 1997; 
  • 12 Höppner W, Dralle H, Brabant G. Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2a.  Hum Mut Suppl. 1 128-130 1998; 
  • 13 Hofstra R MW, Landsvater R M, Cecherini I, Stulp R P, Steiwagen T, Luo Y, Pasini B, Hoppener J WM, Ploos van Amstel H K, Romeo G, Lips C JM, Buys C HCM. A mutation in the RET proto-oncogene associated with endocrie neoplasia type 2B and sporadic thyroid carcinoma.  Nature. 367 375-376 1994; 
  • 14 International RET Mutation Consortium . The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2.  JAMA. 276 1575-1579 1996; 
  • 15 Komminoth P, Kunz E K, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz P U. Analysis of RET proto-oncogene point mutations distinguished heritable from nonheritable medullary thyroid carcinomas.  Cancer. 76 479-489 1995; 
  • 16 Mohammandi M, Schlessinger J, Hubbard S R. Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism.  Cell. 86 577-587 1996; 
  • 17 Mulligan L M, Kwok J BJ, Healey C S, Elsdon M J, Eng C, Gardner E, Love D R, Mole S E, Moore J K, Papi L, Ponder M A, Telenius H, Tunnacliffe A, Ponder B AJ. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2a.  Nature. 363 458-460 1993; 
  • 18 Mulligan L M, Eng C, Healey C S, Clayton D, Kwok J BJ, Gardner E, Ponder M A, Frilling A, Jackson C E, Lehnert H, Neumann H PH, Thibodeau S N, Ponder B AJ. Specific mutations of the RET proto-oncogene are related to disease phenotyp in MEN2a and FMTC.  Nature Genet. 6 70-74 1994; 
  • 19 Pasini A, Geneste O, Legrand P, Schlumberger M, Rossel M, Fournier L, Rudkin B B, Schuffenecker I, Lenoir G M, Billaud M. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain.  Oncogene. 15 393-402 1997; 
  • 20 Santoro M, Carlomagno F, Romano A, Bottaro D P, Dathan N A, Grieco M, Fusco A, Vecchio G, Matoskova B, Kraus M H, Di Fiore P P. Activation of RET as a dominant transforming gene by germline mutations of MEN2a and 2B.  Science. 267 381-383 1995; 
  • 21 Schuffenecker I, Billaud M, Calender A, Chambe B, Ginet N, Calmettes C, Modigliani E, Lenoir G. the GETC . RET proto-oncogene mutations in French MEN2a and FMTC families.  Hum Mol Genet. 3 1939-1943 1994; 
  • 22 Wells S A, Skinner M A. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multple endocrine neoplasia type 2 syndroms.  Exp Clin Endocrinol Diabetes. 106 29-34 1998; 
  • 23 Zheng J, Knighton D R, ten Eyck L F, Karlsson R, Xuong N, Taylor S S, Sowadski J M. Crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MgATP and peptide inhibitor.  Biochemistry. 32 2154-2161 1993; 

Detlef K. BartschM.D. 

Department of Surgery

Philipps-University Marburg

Baldingerstraße

D-35043 Marburg, Germany

Phone: 49/64 21/2866443

Fax: 49/64 21/2868995

Email: bartsch@mailer.uni-marburg.de