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Allelic Loss in Parathyroid Tumors from Individuals Homozygous for Multiple Endocrine Neoplasia Type 1¹

Endocrinology (A.F., A.M., S.F., V.M., M.L.B.) and Surgical (F.T.) Pathology Units, Department of Clinical Physiopathology and Pathology (A.A.) Institute, University of Florence, 50139 Florence; and Division of Endocrinology (R.C., L.F.), Hospital, Verona, Italy 50139

Address all correspondence and requests for reprints to: Maria Luisa Brandi, M.D., Ph.D., Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.

Homozygosity for the multiple endocrine neoplasia type 1 (MEN1) gene mutation was described in two of three affected siblings of a kindred in which both parents and the third daughter were heterozygotes. Surprisingly, in the two homozygotes, the disease history did not differ from the one of the heterozygotes. In the attempt to unravel genetic differences in parathyroid tumorigenesis between homozygotes and heterozygotes, restriction fragment length polymorphism analysis and microsatellite PCR analysis for loss of heterozygosity (LOH) at the MEN1 gene region on chromosome 11q13 was performed in parathyroid tissues removed at surgery from the mother, her heterozygous sister, and the three siblings. Allelic losses were evidenced in the larger glands of each patient, with a similar pattern of chromosome 11q12–13 losses. The somatic mutation consisted of a large loss of genetic material from chromosome 11. No gross differences exist in the 11q12–13 LOH observed between homozygous and heterozygous carriers. Interestingly, one of the parathyroid tumors from one heterozygote exhibited region of skipped LOH at the 11q12–13 region. The region in the depth of the critical interval retained heterozygosity, whereas those flanking it shared LOH. These findings indicate that inactivation of both copies of the MEN1 gene are not sufficient for parathyroid tumor development in MEN 1 patients and that tumor suppressor genes, other than the MEN1 gene on chromosome 11 or on other chromosomes, can be involved in the pathogenesis of parathyroid tumorigenesis in MEN 1 syndrome.

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