title: Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors.
abstract: 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.
authors.affiliation: Endocrine Oncology Laboratory, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: M R
authors.initials: MR
authors.lastname: Pollak
authors.forename: E M
authors.initials: EM
authors.lastname: Brown
authors.forename: A
authors.initials: A
authors.lastname: Arnold
mesh_terms: D000236:Adenoma / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics*; D004252:DNA Mutational Analysis; D005110:Extracellular Space / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D009693:Nucleic Acid Hybridization; D010280:Parathyroid Glands / Q000473:pathology; D010282:Parathyroid Neoplasms / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012260:Ribonucleases
chemical_list: D011956:Receptors, Cell Surface; D012260:Ribonucleases; D002118:Calcium