Journal Article

Mutations in the Ca<sup>2+</sup>-Sensing Receptor Gene Cause Autosomal Dominant and Sporadic Hypoparathyroidism

Jeffrey Baron, Karen K. Winer, Jack A. Yanovski, Adrienne W. Cunningham, Louisa Laue, Donald Zimmerman and Gordon B. Cutler

in Human Molecular Genetics

Volume 5, issue 5, pages 601-606
Published in print May 1996 | ISSN: 0964-6906
Published online May 1996 | e-ISSN: 1460-2083 | DOI:
Mutations in the Ca2+-Sensing Receptor Gene Cause Autosomal Dominant and Sporadic Hypoparathyroidism

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Parathyroid hormone secretion is negatively regulated by a 7-transmembrane domain, G-protein coupled Ca2+-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca2+-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca2+-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca2+-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.

Journal Article.  3256 words.  Illustrated.

Subjects: Genetics and Genomics

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