PARATHYROID MEN1 GENE-MUTATIONS IN RELATION TO CLINICAL CHARACTERISTICS OF NONFAMILIAL PRIMARY HYPERPARATHYROIDISM

Biochemical signs and severity of symptoms of primary hyperparathyroid ism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormaliti es in the parathyroid tumors. Mutations in the recently identified MEN 1 gene at chromosome 11q13 have been found in parathyroid tumors of no nfamilial pHPT. Using microsatellite analysis for loss of heterozygosi ty (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene wa s studied in 49 parathyroid lesions of patients with divergent symptom s, operative findings, histopathological diagnosis, and biochemical si gns of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumo rs, and 6 of them demonstrated previously unrecognized somatic missens e and frameshift deletion mutations of the MEN1 gene. Many of the dete cted mutations would most likely result in a nonfunctional menin prote in, consistent with a tumor suppressor mechanism. Clinical and biochem ical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstrat ion of LOH at 11q13 and MEN1 gene mutations in small parathyroid adeno mas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.