title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
abstract: BACKGROUND
  The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria.
  
  
  METHODS
  We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293).
  
  
  RESULTS
  Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor.
  
  
  CONCLUSIONS
  Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.
authors.affiliation: Medical Research Council Molecular Endocrinology Group, Royal Postgraduate Medical School, London, United Kingdom.
authors.forename: S H
authors.initials: SH
authors.lastname: Pearce
authors.forename: C
authors.initials: C
authors.lastname: Williamson
authors.forename: O
authors.initials: O
authors.lastname: Kifor
authors.forename: M
authors.initials: M
authors.lastname: Bai
authors.forename: M G
authors.initials: MG
authors.lastname: Coulthard
authors.forename: M
authors.initials: M
authors.lastname: Davies
authors.forename: N
authors.initials: N
authors.lastname: Lewis-Barned
authors.forename: D
authors.initials: D
authors.lastname: McCredie
authors.forename: H
authors.initials: H
authors.lastname: Powell
authors.forename: P
authors.initials: P
authors.lastname: Kendall-Taylor
authors.forename: E M
authors.initials: EM
authors.lastname: Brown
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D006996:Hypocalcemia / Q000175:diagnosis / Q000235:genetics*; D007011:Hypoparathyroidism / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000097:blood; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics*; D013577:Syndrome
chemical_list: D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium