Mutational analysis of the extracellular Ca{sup 2+}-sensing receptor gene in human parathyroid tumors

Journal Article · Sun Oct 01 04:00:00 EDT 1995 · Journal of Clinical Endocrinology and Metabolism

DOI:https://doi.org/10.1210/jc.80.11.3107· OSTI ID:443615

Hosokawa, Yoshitaka; Arnold, A ^[1]; Pollak, M R; Brown, E M ^[2]

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1. Massachusetts General Hospital and Harvard Medical School, Boston, MA (United States)
2. Brigham and Women`s Hospital, Boston, MA (United States)

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{sup 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 parathroid hypercellularity. Thus, the Ca{sup 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 Ca{sup 2+} similar to those seen in hyperparathyroidism. Using a ribonuclease A protection assay that has detected multiple mutations in the Ca{sup 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{sup 2+}-sensing receptor gene does not commonly contribute to the pathogenesis of sporadic parathyroid tumors. As such, PTH set-point dysfunction in parathroid tumors may well be secondary to other clonal proliferative defects and/or mutations in other components of the extracellular Ca{sup 2+}-sensing pathway. 29 refs., 2 figs.

• OSTI ID: 443615
• Journal Information: Journal of Clinical Endocrinology and Metabolism, Journal Name: Journal of Clinical Endocrinology and Metabolism Journal Issue: 10 Vol. 80; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
ANIMAL CELLS
CALCIUM
CELL PROLIFERATION
DNA-CLONING
ELECTROPHORESIS
GENE MUTATIONS
GENES
HEREDITARY DISEASES
HYPERPARATHYROIDISM
NEOPLASMS
ONCOGENES
PARATHYROID GLANDS
POLYMERASE CHAIN REACTION
RECEPTORS
SOMATIC MUTATIONS