title: Functional activities of mutant calcium-sensing receptors determine clinical presentations in patients with autosomal dominant hypocalcemia.
abstract: OBJECTIVE
  Autosomal dominant hypocalcemia (ADH) is a congenital isolated hypoparathyroidism caused by activating mutations in the calcium-sensing receptor (CASR) gene. The clinical features of ADH are heterogeneous; some patients are asymptomatic, and others show severe hypocalcemia with Bartter's syndrome. We therefore recruited 12 patients with ADH to clarify the determinants of their clinical presentation.
  
  
  METHODS
  We studied two sporadic and 10 familial cases of ADH. Serum concentrations of calcium, intact PTH, and magnesium (Mg(2+)) were measured in each patient. Fractional excretion of Mg (FE(Mg)) was calculated in spot urine samples. A nuclear factor of activated T cells luciferase assay was used to analyze the responsiveness of each mutant CaSR to extracellular Ca(2+).
  
  
  RESULTS
  Genomic analysis revealed five known activating mutations and a novel mutation, E481K, in the CASR. Patients with the A843E, C131W, or F788C mutation showed hypomagnesemia with elevated FE(Mg). Intact PTH in these patients was consistently near the detection limit. In contrast, patients with the P221L, K47N, or E481K mutation exhibited normal Mg(2+) levels. In these patients, intact PTH increased in response to low calcium, and their maximum intact PTH exceeded the lower limit of the reference range. Functional analysis showed an association between the disease severity and the in vitro activity of the mutant CaSR.
  
  
  CONCLUSIONS
  The functional activity of mutant CaSR determines the serum Mg(2+) level, renal Mg(2+) handling, and intact PTH in patients with ADH. The presence of hypomagnesemia with elevated FE(Mg) may indicate the diagnosis of ADH among patients with PTH-deficient hypoparathyroidism.
authors.affiliation: Division of Nephrology and Endocrinology, Department of Medicine, University of Tokyo Hospital, Tokyo 113-8655, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Michiko
authors.initials: M
authors.lastname: Hori
authors.forename: Manabu
authors.initials: M
authors.lastname: Taguchi
authors.forename: Sumiyo
authors.initials: S
authors.lastname: Watanabe
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukumoto
mesh_terms: D000328:Adult; D002118:Calcium / Q000097:blood; D002648:Child; D005260:Female; D006801:Humans; D053565:Hypercalciuria / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D006996:Hypocalcemia / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D007011:Hypoparathyroidism / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008274:Magnesium / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000097:blood; D010641:Phenotype; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D008274:Magnesium; D002118:Calcium