Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome

Rosa Vargas-Poussou, Chunfa Huang, Philippe Hulin, Pascal Houillier, Xavier Jeunemaître, Michel Paillard, Gabrielle Planelles, Michèle Déchaux, R. Tyler Miller, Corinne Antignac

Research output: Contribution to journalArticle

246 Scopus citations

Abstract

The extracellular Ca2+-sensing receptor (CaSR) plays an essential role in extracellular Ca2+ homeostasis by regulating the rate of parathyroid hormone (PTH) secretion and the rate of calcium reabsorption by the kidney. Activation of the renal CaSR is thought to inhibit paracellular divalent cation reabsorption in the cortical ascending limb (cTAL) both directly and indirectly via a decrease in NaC1 transport. However, in patients with autosomal dominant hypocalcemia (ADH), caused by CaSR gain-of-function mutations, a defect in tubular NaC1 reabsorption with renal loss of NaC1 has not been described so far. This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaC1 balance with secondary hyperaldosteronism and hypokalemia. The kinetics of activation of the L125P mutant receptor expressed in HEK-293 cells, assessed by measuring CaSR-stimulated changes in intracellular Ca2+ and ERK activity, showed a dramatic reduction in the EC50 for extracellular Ca2+ compared with the wild-type and a loss-of-function mutant CaSR (I40F). This study describes the first case of ADH associated with a Bartter-like syndrome. It is herein proposed that the L125P mutation of the CaSR, which represents the most potent gain-of-function mutation reported so far, may reduce NaC1 reabsorption in the cTAL sufficiently to result in renal loss of NaC1 with secondary hyperaldosteronism and hypokalemia.

Original languageEnglish (US)
Pages (from-to)2259-2266
Number of pages8
JournalJournal of the American Society of Nephrology
Volume13
Issue number9
DOIs
StatePublished - Sep 2002

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome'. Together they form a unique fingerprint.

  • Cite this