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A New Germline RET Mutation Apparently Devoid of Transforming Activity Serendipitously Discovered in a Patient with Atrophic Autoimmune Thyroiditis and Primary Ovarian Failure

Divisions of Endocrinology (G.O., G.P., A.C., S.M.), Department of Medical Sciences, Med-Università di Cagliari and Medical Genetics (S.L., C.C.), University of Cagliari, 09042 Monserrato-Cagliari, Italy; Endocrinology and Experimental Oncology (V.D.F., M.S., R.M.M.), "Federico II" University, 80131 Naples, Italy; and Department of Endocrinology (R.E., C.R.), University of Pisa, 56124 Pisa, Italy

Address all correspondence and requests for reprints to: Prof. S. Mariotti, Endocrinology, Department of Medical Sciences, University of Cagliari-Policlinico Universitario, S.S. 554, Bivio per Sestu, 09042 Monserrato-Cagliari, Italy. E-mail: mariotti{at}pacs.unica.it.

Gain-of-function RET mutations are responsible for multiple endocrine neoplasia syndromes (MEN) 2A and 2B and familial medullary thyroid carcinoma (FMTC), whereas loss-of-function mutations are found in Hirschsprung disease. We report a new RET point mutation [R694Q (CGGCAG)], serendipitously found in a 23-yr-old woman with hypothyroidism due to atrophic Hashimoto’s thyroiditis and primary ovarian failure, without altered calcitonin secretion. Familial history and clinical and biochemical evaluation of first-degree relatives were negative for FMTC, MEN 2A and 2B, and Hirschsprung disease. Genetic analysis showed that the mutation was inherited from the mother, who was submitted 2 yr before to thyroidectomy for goitrous Hashimoto’s thyroiditis. Histological revision and immunohistochemical studies documented normal C cell number and morphology. We cloned the mutation in an expression vector encoding a full-length RET protein. The construct was transiently expressed in 293T cells in parallel with a wild-type RET and a C634R MEN 2A-associated RET mutant. Proteins were harvested from transfected cells, and tyrosine phosphorylation levels were assayed. The mutation did not exert significant potentiating effects on RET kinase. A focus assay was also performed on NIH3T3 fibroblasts; the mutant did not exert significant transforming activity.

In conclusion, a new RET mutation was found in two subjects without any evidence of MEN and FMTC. In keeping with clinical data, transfection studies confirmed lack of activating activity. This serendipitous discovery, apparently devoid of oncogenic potential, underscores the problems that may be encountered in genomic studies on RET.