Human Molecular Genetics, Vol 5, 601-606, Copyright © 1996 by Oxford University Press
J Baron, KK Winer, JA Yanovski, AW Cunningham, L Laue, D Zimmerman and GB Cutler Jr
Parathyroid hormone secretion is negatively regulated by a 7- transmembrane
domain, G-protein coupled Ca(2+)-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
Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of
50 normal controls had either mutation. We also identified a de novo,
missense Ca(2+)-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 Ca(2+)-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.
ARTICLES
Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1862, USA.
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