title: Novel activating mutation of human calcium-sensing receptor in a family with autosomal dominant hypocalcaemia.
abstract: BACKGROUND
  Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations in the calcium sensing receptor gene (CaR) and characterised by mostly asymptomatic mild to moderate hypocalcaemia with low, inappropriately serum concentration of PTH.
  
  
  OBJECTIVE
  The purpose of the present study was to biochemically and functionally characterise a novel mutation of CaR.
  
  
  METHODS
  A female proband presenting with hypocalcaemia was diagnosed to have "idiopathic hypoparathyroidism" at the age of 10 with a history of muscle pain and cramps. Further examinations demonstrated hypocalcaemia in nine additional family members, affecting three generations.
  
  
  METHODS
  P136L CaR mutation was predicted to cause gain of function of CaR.
  
  
  RESULTS
  Affected family members showed relevant hypocalcaemia (mean ± SD; 1.9 ± 0.1 mmol/l). Patient history included mild seizures and recurrent nephrolithiasis. Genetic analysis confirmed that hypocalcaemia cosegregated with a heterozygous mutation at codon 136 (CCC → CTC/Pro → Leu) in exon 3 of CaR confirming the diagnosis of ADH. For in vitro studies P136L mutant CaR was generated by site-directed mutagenesis and examined in transiently transfected HEK293 cells. Extracellular calcium stimulation of transiently transfected HEK293 cells showed significantly increased intracellular Ca(2+) mobilisation and MAPK activity for mutant P136L CaR compared to wild type CaR.
  
  
  CONCLUSIONS
  The present study gives insight about a novel activating mutation of CaR and confirms that the novel P136L-CaR mutation is responsible for ADH in this family.
authors.affiliation: Department of Endocrinology and Diabetology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany; Department of Medicine V, University of Heidelberg, INF 410, 69120 Heidelberg, Germany. Electronic address: natalia.baran@med.uni-heidelberg.de.
authors.forename: Natalia
authors.initials: N
authors.lastname: Baran
authors.affiliation: Institut of Pharmacology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: ter Braak
authors.affiliation: Department of Medicine V, University of Heidelberg, INF 410, 69120 Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Saffrich
authors.affiliation: Pediatric Endocrinology Division, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Woelfle
authors.affiliation: Department of Endocrinology and Diabetology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Schmitz
mesh_terms: D000328:Adult; D002118:Calcium / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003062:Codon; D005091:Exons; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D053565:Hypercalciuria / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006996:Hypocalcemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007011:Hypoparathyroidism / Q000150:complications / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010281:Parathyroid Hormone / Q000172:deficiency / Q000235:genetics*; D010375:Pedigree; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D014162:Transfection
chemical_list: C095550:CASR protein, human; D003062:Codon; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002118:Calcium
keywords: ADH; Activating mutation; CaR; Hypocalcaemia; MAPK