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A Novel Val⁶⁴⁸Ile Substitution in RET Protooncogene Observed in a Cys⁶³⁴Arg Multiple Endocrine Neoplasia Type 2A Kindred Presenting with an Adrenocorticotropin-Producing Pheochromocytoma

Endocrine Genetics Unit (A.B.N., M.C.L.E., S.P.A.T.), Department of Endocrinology, and Laboratory of Genetics and Molecular Cardiology (A.C.P., J.E.K.), University of Sao Paulo School of Medicine, 01246-903 Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Dr. Adriana B. Nunes, University of Sao Paulo School of Medicine, Endocrine Genetics Unit, Avenue Dr. Arnaldo 455, 5th Floor, 02146-903 Sao Paulo, Brazil. E-mail: adr001{at}uol.com.br.

Abstract

Multiple endocrine neoplasia type 2 (MEN 2) comprises a heterogeneous group of neoplasic disorders that most commonly have a single missense substitution of the RET protooncogene (RET) involving exons 10 and 11. It was previously reported a MEN 2A kindred in which the father presented with a rare phenotype consisting of bilateral ACTH-producing pheochromocytoma and medullary thyroid carcinoma. We recently performed mutational analysis of the father and his 4 children using a denaturing gradient gel electrophoresis approach and PCR-amplified genomic DNA, followed by direct sequencing or restriction fragment length polymorphism testing. All 4 children showed a RET sequence variation. The common exon 11 Cys⁶³⁴Arg RET mutation was present in 2 of the 4 children who had undergone thyroidectomy for C cell disease. The remaining 2 children, who did not harbor the Cys⁶³⁴Arg mutation and are negative for C cell and adrenal disease, carry a previously unreported Val⁶⁴⁸Ile missense change in RET exon 11. This novel substitution was not found in the unaffected mother or in 200 control alleles. Both RET variants were present in the father affected with MEN 2A and the unusual ACTH-producing pheochromocytoma. We speculate that the double RET mutation may have modified and contributed to the rare MEN 2A phenotype in the father.

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