MUTATIONAL ANALYSIS OF THE EXTRACELLULAR CA2-SENSING RECEPTOR GENE INHUMAN PARATHYROID TUMORS()

Despite recent progress, such as the identification of PRAD1/cyclin D1 as a parathyroid oncogene, it is likely that many genes involved in t he molecular pathogenesis of parathyroid tumors remain unknown. Indivi duals heterozygous for inherited mutations in the extracellular Ca2+-s ensing receptor gene that reduce its biological activity exhibit a dis order termed familial hypocalciuric hypercalcemia or familial benign h ypercalcemia, which is characterized by reduced responsiveness of para thyroid and kidney to calcium and by PTH-dependent hypercalcemia. Thos e who are homozygous for such mutations present with neonatal severe h yperparathyroidism and have marked parathyroid hypercellularity. Thus, the Ca2+-sensing receptor gene is a candidate parathyroid tumor suppr essor gene, with inactivating mutations plausibly explaining set-point abnormalities in the regulation of both parathyroid cellular prolifer ation 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 Ca2+-sensing receptor gene in fami lial hypocalciuric hypercalcemia and covers more than 90% of its codin g region, we sought somatic mutations in this gene in a total of 44 hu man parathyroid tumors (23 adenomas, 4 carcinomas, 5 primary hyperplas ias, and 12 secondary hyperplasias). No such mutations were detected i n these 44 tumors. Thus, our studies suggest that somatic mutation of the Ca2+-sensing receptor gene does not commonly contribute to the pat hogenesis of sporadic parathyroid tumors. As such, PTH set-point dysfu nction in parathyroid tumors may well be secondary to other clonal pro liferative defects and/or mutations in other components of the extrace llular Ca2+-sensing pathway.