2. Academic Validation
  3. Novel activating mutation of human calcium-sensing receptor in a family with autosomal dominant hypocalcaemia

Novel activating mutation of human calcium-sensing receptor in a family with autosomal dominant hypocalcaemia

  • Mol Cell Endocrinol. 2015 May 15;407:18-25. doi: 10.1016/j.mce.2015.02.021.
Natalia Baran 1,  Michael ter Braak 2,  Rainer Saffrich 3,  Joachim Woelfle 4,  Udo Schmitz 5
Affiliations

Affiliations

  • 1 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: [email protected].
  • 2 Institut of Pharmacology, University of Essen, Hufelandstr. 55, 45122 Essen, Germany.
  • 3 Department of Medicine V, University of Heidelberg, INF 410, 69120 Heidelberg, Germany.
  • 4 Pediatric Endocrinology Division, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany.
  • 5 Department of Endocrinology and Diabetology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
PMID: 25766501 DOI: 10.1016/j.mce.2015.02.021
Abstract

Introduction: 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.

Patients: 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.

Main outcome measure: 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.

Keywords

ADH; Activating mutation; CaR; Hypocalcaemia; MAPK.

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