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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 770-774
Copyright © 1998 by The Endocrine Society

Original Studies

A New Hot Spot for Mutations in the ret Protooncogene Causing Familial Medullary Thyroid Carcinoma and Multiple Endocrine Neoplasia Type 2A1

Ilona Berndt, Marlene Reuter, B. Saller, Karin Frank-Raue, P. Groth, M. Grußendorf, F. Raue, M. M. Ritter and W. Höppner

Institute for Hormone and Fertility Research, University of Hamburg (I.B., M.R., W.H.), Hamburg; the Division of Endocrinology, Department of Medicine, University of Essen (B.S.), Essen; Endokrinologische Praxisgemeinschaft (K.F.-R., F.R.), Heidelberg; Klinik und Poliklinik für Nuklearmedizin, University of Rostock (P.G.); Endokrinologische Praxisgemeinschaft (M.G.), Stuttgart; and Medical Department II, Klinikum Groshadern, University of Munich (M.M.R.), Munich, Germany

Address all correspondence and requests for reprints to: Wolfgang Höppner Ph.D., Institute for Hormone and Fertility Research, University of Hamburg, Molecular Diagnostic Group, Grandweg 64, D-22529 Hamburg, Germany. E-mail: hoeppner.wolfgang{at}Leidenberger.de

One hundred and eighty-one families with multiple endocrine neoplasia type 2A (MEN-2A) or familial medullary thyroid carcinoma (FMTC) have been investigated for mutations in the ret protooncogene in Germany. In 8 families with FMTC or MEN-2A, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11 of the ret protooncogene. DNA sequencing of additional exons (no. 13–15) revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors.

Two different mutations in codon 790 (TTG->TTT, TTG->TTC; Leu790Phe) and one mutation in codon 791 (TAT->TTT; Tyr791Phe) created a phenylalanine residue.

We conclude that codons 790 and 791 of the ret protooncogene represent a new hot spot for FMTC/MEN-2A causing mutations. With the discovery of these considerably common mutations in codons 790 and 791 and the identification of some rare mutations, 100% of the German FMTC/MEN-2A families could be characterized by a mutation in the ret protooncogene.




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