HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 10, 7656-7667, March 9, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/10/7656    most recent M611117200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chubanov, V. Articles by Gudermann, T. Search for Related Content PubMed PubMed Citation Articles by Chubanov, V. Articles by Gudermann, T. Social Bookmarking                      What's this?

Hypomagnesemia with Secondary Hypocalcemia due to a Missense Mutation in the Putative Pore-forming Region of TRPM6^*

Vladimir Chubanov, Karl P. Schlingmann, Janine Wäring, Jolanta Heinzinger, Silke Kaske, Siegfried Waldegger, Michael Mederos y Schnitzler, and Thomas Gudermann¹

From the Institute for Pharmacology and Toxicology and the University Children's Hospital, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, 35033 Marburg, Germany

Hypomagnesemia with secondary hypocalcemia is an autosomal recessive disorder caused by mutations in the TRPM6 gene. Current experimental evidence suggests that TRPM6 may function in a specific association with TRPM7 by means of heterooligomeric channel complex formation. Here, we report the identification and functional characterization of a new hypomagnesemia with secondary hypocalcemia missense mutation in TRPM6. The affected subject presented with profound hypomagnesemia and hypocalcemia caused by compound heterozygous mutation in the TRPM6 gene: 1208(-1)G > A affecting the acceptor splice site preceding exon 11, and 3050C > G resulting in the amino acid change (P1017R) in the putative pore-forming region of TRPM6. To assess the functional consequences of the P1017R mutation, TRPM6^P1017R and wild-type TRPM6 were co-expressed with TRPM7 in Xenopus oocytes and HEK 293 cells, and currents were assessed by two-electrode voltage clamp and whole cell patch clamp measurements, respectively. Co-expression of wild-type TRPM6 and TRPM7 resulted in a significant increase in the amplitude of TRPM7-like currents. In contrast, TRPM6^P1017R suppressed TRPM7 channel activity. In line with these observations, TRPM7, containing the corresponding mutation P1040R, displayed a dominant-negative effect upon co-expression with wild-type TRPM7. Confocal microscopy and fluorescence resonance energy transfer recordings demonstrated that the P1017R mutation neither affects assembly of TRPM6 with TRPM7, nor co-trafficking of heteromultimeric channel complexes to the cell surface. We conclude that a functional defect in the putative pore of TRPM6/7 channel complexes is sufficient to impair body magnesium homeostasis.

Received for publication, December 4, 2006

^* This work was supported by the Deutsche Forschungsgemeinschaft and the German Kidney Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondence should be addressed: Tel.: 49-6421-2865-000; Fax: 49-6421-2865-600; E-mail: guderman{at}staff.uni-marburg.de.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. Cao, J. van der Wijst, A. van der Kemp, F. van Zeeland, R. J. Bindels, and J. G. Hoenderop Regulation of the Epithelial Mg2+ Channel TRPM6 by Estrogen and the Associated Repressor Protein of Estrogen Receptor Activity (REA) J. Biol. Chem., May 29, 2009; 284(22): 14788 - 14795. [Abstract] [Full Text] [PDF]

				R. T. Alexander, J. G. Hoenderop, and R. J. Bindels Molecular Determinants of Magnesium Homeostasis: Insights from Human Disease J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1451 - 1458. [Abstract] [Full Text] [PDF]

				Q. Sha, W. Pearson, L. C. Burcea, D. A. Wigfall, P. H. Schlesinger, C. G. Nichols, and R. W. Mercer Human FXYD2 G41R mutation responsible for renal hypomagnesemia behaves as an inward-rectifying cation channel Am J Physiol Renal Physiol, July 1, 2008; 295(1): F91 - F99. [Abstract] [Full Text] [PDF]

				M. Mederos y Schnitzler, J. Waring, T. Gudermann, and V. Chubanov Evolutionary determinants of divergent calcium selectivity of TRPM channels FASEB J, May 1, 2008; 22(5): 1540 - 1551. [Abstract] [Full Text] [PDF]

				R. M. Touyz Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1103 - H1118. [Abstract] [Full Text] [PDF]

				J. Xing, X. Yan, A. Estevez, and K. Strange Highly Ca2+-selective TRPM Channels Regulate IP3-dependent Oscillatory Ca2+ Signaling in the C. elegans Intestine J. Gen. Physiol., February 25, 2008; 131(3): 245 - 255. [Abstract] [Full Text] [PDF]

				A. Goytain and G. A. Quamme Identification and characterization of a novel family of membrane magnesium transporters, MMgT1 and MMgT2 Am J Physiol Cell Physiol, February 1, 2008; 294(2): C495 - C502. [Abstract] [Full Text] [PDF]