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Identification of a Novel Point Mutation in the RET Gene (Ala883Thr), Which Is Associated with Medullary Thyroid Carcinoma Phenotype Only in Homozygous Condition

Departments of Endocrinology and Metabolism (R.E., B.C., C.R., L.A., P.P., A.P.), Oncology (F.B., C.U.), and Surgery (P.M., P.B.), University of Pisa, 56124 Pisa, Italy; Department of Pathology (R.C., Y.N.), University of Cincinnati, Cincinnati, Ohio 45267; and AMBISEN Center, High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems (A.P.), University of Pisa, 56100 Pisa, Italy

Address all correspondence and requests for reprints to: R. Elisei, M.D., Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: relisei{at}endoc.med.unipi.it.

The RET protooncogene mutations responsible for multiple endocrine neoplasia type 2 are inherited as autosomic dominant traits. We describe here a novel germline homozygous mutation in exon 15 of the RET gene that determines an amino acid substitution (Ala->Thr) at codon 883. The index case was a 51-yr-old patient with an apparently sporadic form of medullary thyroid cancer (MTC). RET gene mutations screening was performed in exons 10, 11, 13, 14, 15, and 16 by automatic sequence analysis. An unexpected homozygous GCT->ACT point mutation was found at codon 883 in exon 15 and confirmed by restriction analysis (Alu I). The presence of the two chromosomes 10 was confirmed by fluorescence in situ hybridization analysis on lymphocytes. As expected on the basis of the homozygosity of the index case, the parents were consanguineous (second-degree cousins). Eight relatives were further investigated: the mother, two sisters, and the son were positive for heterozygous RET mutation. The mother (82 yr old) showed a nodular goiter but was negative both for basal and pentagastrin stimulated calcitonin. The young son (15 yr old) and the two sisters (63 and 58 yr old) did not show any clinical and/or biochemical sign of MTC. One brother (59 yr old) was negative both for RET mutation and clinical/biochemical examination. The other brother, 56 yr of age, was positive for both homozygous RET mutation and serum calcitonin. When operated, the histological examination of the thyroid showed the presence of MTC and C cell hyperplasia.

In conclusion, we identified a new germline RET gene mutation during a routine RET gene screening of an apparently sporadic MTC case. This mutation showed a very low transforming activity as demonstrated by the absence of MTC phenotype in heterozygous subjects. The possibility that the homozygous gene carriers were indeed carrying a germline loss of heterozygosity was excluded by fluorescence in situ hybridization analysis for RET gene performed on lymphocytes derived from one homozygous patient. The analysis of several RET polymorphisms also confirmed the presence of two mutated alleles in MTC affected patients and both mutated and wild-type allele in heterozygous subjects.

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