CNNM2, Encoding a Basolateral Protein Required for Renal Mg²⁺ Handling, Is Mutated in Dominant Hypomagnesemia

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• 作者：Marchel Stuiver¹ ; ² ; Sergio Lainez³ ; Constanze Will¹ ; ² ; Sara Terryn⁴ ; Dorothee G&#xfc ; nzel⁵ ; Huguette Debaix⁴ ; Kerstin Sommer¹ ; ² ; Kathrin Kopplin¹ ; ² ; Julia Thumfart¹ ; ² ; Nicole  ; B. Kampik⁶ ; Uwe Querfeld¹ ; ² ; Thomas  ; E. Willnow⁷ ; Vladimí ; r Ně ; mec⁸ ; Carsten  ; A. Wagner⁶ ; Joost  ; G. Hoenderop³ ; Olivier Devuyst⁴ ; ⁶ ; Nine  ; V.A.M. Knoers⁹ ; René ;   ; J. Bindels³ ; Iwan  ; C. Meij⁷ ; ¹⁰ ; Dominik M&#xfc ; ller¹ ; ² ; ¹⁰ ; ^{dominik.mueller@charite.de}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 March 2011
• 年：2011
• 卷：88
• 期：3
• 页码：333-343
• 全文大小：1156 K

文摘

Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg²⁺) wasting, which may lead to symptoms of Mg²⁺ depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg²⁺ (re)absorption, particularly the luminal uptake of Mg²⁺ along the nephron, has benefitted from positional cloning approaches in families with Mg²⁺ reabsorption disorders; however, basolateral Mg²⁺ transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg²⁺ handling in patients of two unrelated families with unexplained dominant hypomagnesemia. In the kidney, CNNM2 was predominantly found along the basolateral membrane of distal tubular segments involved in Mg²⁺ reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg²⁺-sensitive Na⁺ currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg²⁺ concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg²⁺ concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg²⁺, and its basolateral localization signify a critical role for CNNM2 in epithelial Mg²⁺ transport.