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Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family

Nature Genetics volume 31, pages 166–170 (2002)Cite this article

Abstract

Magnesium is an essential ion involved in many biochemical and physiological processes. Homeostasis of magnesium levels is tightly regulated and depends on the balance between intestinal absorption and renal excretion. However, little is known about specific proteins mediating transepithelial magnesium transport. Using a positional candidate gene approach, we identified mutations in TRPM6 (also known as CHAK2), encoding TRPM6, in autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH, OMIM 602014)1,2, previously mapped to chromosome 9q22 (ref. 3). The TRPM6 protein is a new member of the long transient receptor potential channel (TRPM) family4 and is highly similar to TRPM7 (also known as TRP-PLIK), a bifunctional protein that combines calcium- and magnesium-permeable cation channel properties with protein kinase activity5,6,7. TRPM6 is expressed in intestinal epithelia and kidney tubules. These findings indicate that TRPM6 is crucial for magnesium homeostasis and implicate a TRPM family member in human disease.

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Figure 1: Haplotype analysis of families F1, F2 and F5.
Figure 2: Characterization of TRPM6.
Figure 3: Sequence analysis and tissue distribution of TRPM6.
Figure 4: In situ hybridization analysis of TRPM6 expression.
Figure 5: Intestinal magnesium absorption.

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References

  1. Paunier, L., Radde, I.C., Kooh, S.W., Conen, P.E. & Fraser, D. Primary hypomagnesemia with secondary hypocalcemia in an infant. Pediatrics 41, 385–402 (1968).

    CAS  PubMed  Google Scholar 

  2. Shalev, H., Phillip, M., Galil, A., Carmi, R. & Landau, D. Clinical presentation and outcome in primary familial hypomagnesaemia. Arch. Dis. Child. 78, 127–130 (1998).

    Article  CAS  Google Scholar 

  3. Walder, R.Y. et al. Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint. Hum. Mol. Genet. 6, 1491–1497 (1997).

    Article  CAS  Google Scholar 

  4. Ryazanova, L.V., Pavur, K.S., Petrov, A.N., Dorovkov, M.V. & Ryazanov, A.G. Novel type of signaling molecules: protein kinases covalently linked with ion channels. Mol. Biol. 35, 271–283 (2001).

    Article  CAS  Google Scholar 

  5. Nadler, M.J. et al. LTRPC7 is a Mg-ATP-regulated divalent cation channel required for cell viability. Nature 411, 590–595 (2001).

    Article  CAS  Google Scholar 

  6. Runnels, L.W., Yue, L. & Clapham, D.E. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291, 1043–1047 (2001).

    Article  CAS  Google Scholar 

  7. Ryazanov, A.G. et al. Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. Proc. Natl Acad. Sci. USA 94, 4884–4889 (1997).

    Article  CAS  Google Scholar 

  8. Anast, C.S., Mohs, J.M., Kaplan, S.L. & Burns, T.W. Evidence for parathyroid failure in magnesium deficiency. Science 177, 606–608 (1972).

    Article  CAS  Google Scholar 

  9. Milla, P.J., Aggett, P.J., Wolff, O.H. & Harries, J.T. Studies in primary hypomagnesaemia: evidence for defective carrier-mediated small intestinal transport of magnesium. Gut 20, 1028–1033 (1979).

    Article  CAS  Google Scholar 

  10. Matzkin, H., Lotan, D. & Boichis, H. Primary hypomagnesemia with a probable double magnesium transport defect. Nephron 52, 83–86 (1989).

    Article  CAS  Google Scholar 

  11. Cole, D.E. & Quamme, G.A. Inherited disorders of renal magnesium handling. J. Am. Soc. Nephrol. 11, 1937–1947 (2000).

    CAS  PubMed  Google Scholar 

  12. Walder, R.Y. et al. Hypomagnesemia with secondary hypocalcemia (HSH): narrowing the disease region on chromosome 9. Am. J. Hum. Genet. 65, 451 (1999).

  13. Harteneck, C., Plant, T.D. & Schultz, G. From worm to man: three subfamilies of TRP channels. Trends Neurosci. 23, 159–166 (2000).

    Article  CAS  Google Scholar 

  14. Shapiro, M.B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).

    Article  CAS  Google Scholar 

  15. Quamme, G.A. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 52, 1180–1195 (1997).

    Article  CAS  Google Scholar 

  16. Fine, K.D., Santa Ana, C.A., Porter, J.L. & Fordtran, J.S. Intestinal absorption of magnesium from food and supplements. J. Clin. Invest. 88, 396–402 (1991).

    Article  CAS  Google Scholar 

  17. Kayne, L.H. & Lee, D.B. Intestinal magnesium absorption. Miner. Electrolyte Metab. 19, 210–217 (1993).

    CAS  PubMed  Google Scholar 

  18. Walder, R.Y. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nature Genet. 31 (2002); advance online publication, 28 May 2002 (DOI:10.1038/ng901).

  19. Simon, D.B. et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285, 103–106 (1999).

    Article  CAS  Google Scholar 

  20. Meij, I.C. et al. Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase γ-subunit. Nature Genet. 26, 265–266 (2000).

    Article  CAS  Google Scholar 

  21. Duncan, L.M. et al. Melastatin expression and prognosis in cutaneous malignant melanoma. J. Clin. Oncol. 19, 568–576 (2001).

    Article  CAS  Google Scholar 

  22. Perraud, A.L. et al. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411, 595–599 (2001).

    Article  CAS  Google Scholar 

  23. Cahalan, M.D. Cell biology. Channels as enzymes. Nature 411, 542–543 (2001).

    Article  CAS  Google Scholar 

  24. Challa, A., Papaefstathiou, I., Lapatsanis, D. & Tsolas, O. Primary idiopathic hypomagnesemia in two female siblings. Acta Paediatr. 84, 1075–1078 (1995).

    Article  CAS  Google Scholar 

  25. Konrad, M. et al. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J. Am. Soc. Nephrol. 11, 1449–1459 (2000).

    CAS  PubMed  Google Scholar 

  26. Andre, E. et al. Disruption of retinoid-related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J. 17, 3867–3877 (1998).

    Article  CAS  Google Scholar 

  27. Reddy, S. et al. Isolation and characterization of a cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption. J. Cell Physiol. 177, 636–645 (1998).

    Article  CAS  Google Scholar 

  28. Koizumi, K. et al. Cloning and expression of uridine/cytidine kinase cDNA from human fibrosarcoma cells. Int. J. Mol. Med. 8, 273–278 (2001).

    CAS  PubMed  Google Scholar 

  29. Weber, S. et al. Primary gene structure and expression studies of rodent paracellin-1. J. Am. Soc. Nephrol. 12, 2664–2672 (2001).

    CAS  PubMed  Google Scholar 

  30. Klingel, K. et al. Ongoing enterovirus-induced myocarditis is associated with persistent heart muscle infection: quantitative analysis of virus replication, tissue damage, and inflammation. Proc. Natl Acad. Sci. USA 89, 314–318 (1992).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families for participating in this study, U. Pechmann and P. Barth for excellent technical assistance, C. Antignac, R. Preisig-Müller, C. Derst and N. Jeck for helpful discussions and C. Loirat, D. Lotan, W. Scheurlen, A. Siamopoulou, S. Alfandaki, G. Celsi and A. Kernell for providing clinical data. S.W., H.W.S. and M.K. were supported by the Deutsche Forschungsgemeinschaft. S.W. was supported by the Kempkes-Stiftung, University of Marburg. L.N.N. and S.N. were supported by the Danish National Research Foundation.

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Author notes

  1. Karl P. Schlingmann and Stefanie Weber: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Philipps University of Marburg, Deutschhausstrasse 12, Marburg, D-35037, Germany

    Karl P. Schlingmann, Stefanie Weber, Melanie Peters, Martin Sassen, Siegfried Waldegger, Hannsjörg W. Seyberth & Martin Konrad

  2. Water and Salt Research Center, Institute of Anatomy, University of Aarhus, Denmark

    Lene Niemann Nejsum & Søren Nielsen

  3. Department of Physiology I, University of Regensburg, Germany

    Helga Vitzthum

  4. Department of Molecular Pathology, University Hospital, Tübingen, Germany

    Karin Klingel

  5. University Children's Hospital, Mannheim, Germany

    Markus Kratz

  6. Robert Debré Hospital, Paris, France

    Elie Haddad

  7. Department of Pediatrics, Karolinska Institute, Huddinge University, Stockholm, Sweden

    Ellinor Ristoff

  8. Department of Nephrology, The Chaim Sheba Medical Center, Ramat-Gan, Israel

    Dganit Dinour

  9. Laboratory of General Biology-Genetics, University of Ioannina, Greece

    Maria Syrrou

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Correspondence to Martin Konrad.

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Schlingmann, K., Weber, S., Peters, M. et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31, 166–170 (2002). https://doi.org/10.1038/ng889

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