Journal of Clinical Endocrinology & Metabolism, Vol 80, 3107-3110, Copyright © 1995 by Endocrine Society

ARTICLES

Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors

Y Hosokawa, MR Pollak, EM Brown and A Arnold
Endocrine Oncology Laboratory, Massachusetts General Hospital, Boston 02114, USA.

Despite recent progress, such as the identification of PRAD1/cyclin D1 as a parathyroid oncogene, it is likely that many genes involved in the molecular pathogenesis of parathyroid tumors remain unknown. Individuals heterozygous for inherited mutations in the extracellular Ca(2+)-sensing receptor gene that reduce its biological activity exhibit a disorder termed familial hypocalciuric hypercalcemia or familial benign hypercalcemia, which is characterized by reduced responsiveness of parathyroid and kidney to calcium and by PTH- dependent hypercalcemia. Those who are homozygous for such mutations present with neonatal severe hyperparathyroidism and have marked parathyroid hypercellularity. Thus, the Ca(2+)-sensing receptor gene is a candidate parathyroid tumor suppressor gene, with inactivating mutations plausibly explaining set-point abnormalities in the regulation of both parathyroid cellular proliferation and PTH secretion by extracellular Ca2+ similar to those seen in hyperparathyroidism. Using a ribonuclease A protection assay that has detected multiple mutations in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and covers more than 90% of its coding region, we sought somatic mutations in this gene in a total of 44 human parathyroid tumors (23 adenomas, 4 carcinomas, 5 primary hyperplasias, and 12 secondary hyperplasias). No such mutations were detected in these 44 tumors. Thus, our studies suggest that somatic mutation of the Ca(2+)- sensing receptor gene does not commonly contribute to the pathogenesis of sporadic parathyroid tumors. As such, PTH set-point dysfunction in parathyroid tumors may well be secondary to other clonal proliferative defects and/or mutations in other components of the extracellular Ca(2+)-sensing pathway.

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