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

• Published in: American journal of human genetics Vol. 88; no. 3; pp. 333 - 343
• Main Authors: STUIVER, Marchel, LAINEZ, Sergio, QUERFELD, Uwe, WILLNOW, Thomas E, NEMEC, Vladimir, WAGNER, Carsten A, HOENDEROP, Joost G, DEVUYST, Olivier, KNOERS, Nine V. A. M, BINDELS, René J, MEIJ, Iwan C, MÜLLER, Dominik, WILL, Constanze, TERRYN, Sara, GÜNZEL, Dorothee, DEBAIX, Huguette, SOMMER, Kerstin, KOPPLIN, Kathrin, THUMFART, Julia, KAMPIK, Nicole B
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Cell Press 11.03.2011; Elsevier
• Subjects: Amino Acid Sequence; Amino Acid Substitution - genetics; Animals; Base Sequence; Biological and medical sciences; Cation Transport Proteins - chemistry; Cation Transport Proteins - genetics; Cyclins - chemistry; Cyclins - genetics; Electrophysiological Phenomena - drug effects; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes, Dominant - genetics; Genetics of eukaryotes. Biological and molecular evolution; HEK293 Cells; Humans; Immunohistochemistry; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Magnesium - metabolism; Magnesium - pharmacology; Magnesium Deficiency - genetics; Magnesium Deficiency - pathology; Male; Medical genetics; Medical sciences; Metabolic diseases; Metals (hemochromatosis...); Mice; Molecular and cellular biology; Molecular Sequence Data; Mutation - genetics; Nephrons - drug effects; Nephrons - metabolism; Nephrons - pathology; Other metabolic disorders; Pedigree; Up-Regulation - drug effects; Human; Hydroelectrolytic balance disorder; Metabolic disorder; Genetics; Dominant character; Magnesium; Inorganic element; Hypomagnesemia; Protein; Kidney; Handling
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.02.005

Familial hypomagnesemia is a rare human disorder caused by renal or intestinal magnesium (Mg(2+)) wasting, which may lead to symptoms of Mg(2+) depletion such as tetany, seizures, and cardiac arrhythmias. Our knowledge of the physiology of Mg(2+) (re)absorption, particularly the luminal uptake of Mg(2+) along the nephron, has benefitted from positional cloning approaches in families with Mg(2+) reabsorption disorders; however, basolateral Mg(2+) transport and its regulation are still poorly understood. Here, by using a candidate screening approach, we identified CNNM2 as a gene involved in renal Mg(2+) 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 Mg(2+) reabsorption. The basolateral localization of endogenous and recombinant CNNM2 was confirmed in epithelial kidney cell lines. Electrophysiological analysis showed that CNNM2 mediated Mg(2+)-sensitive Na(+) currents that were significantly diminished in mutant protein and were blocked by increased extracellular Mg(2+) concentrations. Our data support the findings of a recent genome-wide association study showing the CNNM2 locus to be associated with serum Mg(2+) concentrations. The mutations found in CNNM2, its observed sensitivity to extracellular Mg(2+), and its basolateral localization signify a critical role for CNNM2 in epithelial Mg(2+) transport.