title: Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations of the Ca(2+)-sensing receptor.
abstract: Activating mutations of the Ca(2+)-sensing receptor (CaR) gene have been identified in families with autosomal dominant hypoparathyroidism and in one patient with sporadic hypoparathyroidism. Here, we describe two additional patients with sporadic hypoparathyroidism. One patient presented with mild symptoms at age 18 yr; the other was severely symptomatic from infancy. A heterozygous missense mutation was identified in each patient. One mutation (L773R) involved the fifth transmembrane domain of the CaR, the other (N118K) affected the amino-terminal, extracellular domain. In both cases, the probands' parents lacked the mutation, indicating that the mutations arose de novo. In expression studies the mutations shifted the concentration-response curve to the left and increased maximal activity. We conclude that 1) sporadic hypoparathyroidism can be caused by de novo gain-of-function mutations of the CaR; 2) the phenotype can vary from mild to life-threatening hypocalcemia; 3) gain-of-function mutations can involve not only extracellular regions, as previously reported, but also transmembrane domains of the CaR; and 4) the mechanism of activation can involve both increased receptor sensitivity to Ca2+ and increased maximal signal transduction.
authors.affiliation: Developmental Endocrinology Branch, National Institute of Child Health and Human Development Bethesda, Maryland 20892, USA. delucaF@cc1.nichd.nih.gov
authors.forename: F
authors.initials: F
authors.lastname: De Luca
authors.forename: K
authors.initials: K
authors.lastname: Ray
authors.forename: E E
authors.initials: EE
authors.lastname: Mancilla
authors.forename: G F
authors.initials: GF
authors.lastname: Fan
authors.forename: K K
authors.initials: KK
authors.lastname: Winer
authors.forename: P
authors.initials: P
authors.lastname: Gore
authors.forename: A M
authors.initials: AM
authors.lastname: Spiegel
authors.forename: J
authors.initials: J
authors.lastname: Baron
mesh_terms: D000328:Adult; D001322:Autoanalysis; D015153:Blotting, Western; D002462:Cell Membrane / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D006801:Humans; D007011:Hypoparathyroidism / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014162:Transfection
chemical_list: D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface