title: Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism.
abstract: 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.
authors: Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1862, USA.
authors: J
authors: J
authors: Baron
authors: K K
authors: KK
authors: Winer
authors: J A
authors: JA
authors: Yanovski
authors: A W
authors: AW
authors: Cunningham
authors: L
authors: L
authors: Laue
authors: D
authors: D
authors: Zimmerman
authors: G B
authors: GB
authors: Cutler
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002648:Child; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
chemical_list: D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium