Familial hypomagnesemia with secondary hypocalcemia (OMIM 602014) is an autosomal recessive disease that results in electrolyte abnormalities shortly after birth1,2,3,4,5,6. Affected individuals show severe hypomagnesemia and hypocalcemia, which lead to seizures and tetany. The disorder has been thought to be caused by a defect in the intestinal absorption of magnesium, rather than by abnormal renal loss of magnesium. Restoring the concentrations of serum magnesium to normal values by high-dose magnesium supplementation can overcome the apparent defect in magnesium absorption and in serum concentrations of calcium. Life-long magnesium supplementation is required to overcome the defect in magnesium handling by these individuals1,3,4. We previously mapped the gene locus to chromosome 9q in three large inbred kindreds from Israel2. Here we report that mutation of TRPM6 causes hypomagnesemia with secondary hypocalcemia and show that individuals carrying mutations in this gene have abnormal renal magnesium excretion.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
Abdulrazzaq, Y.M., Smigura, F.C. & Wettrell, G. Primary infantile hypomagnesaemia; report of two cases and review of literature. Eur. J. Pediatr. 148, 459–461 (1989).
Challa, A., Papaefstathiou, I., Lapatsanis, D. & Tsolas, O. Primary idiopathic hypomagnesemia in two female siblings. Acta Paediatr. 84, 1075–1078 (1995).
Yamamoto, T., Kabata, H., Yagi, R., Takashima, M. & Itokawa, Y. Primary hypomagnesemia with secondary hypocalcemia. Report of a case and review of the world literature. Magnesium 4, 153–164 (1985).
Meyer, P. & Boettger, M.B. Familial hypomagnesaemia with secondary hypocalcaemia: a new case that indicates autosomal recessive inheritance. J. Inherit. Metab. Dis. 24, 875–876 (2001).
Runnels, L.W., Yue, L. & Clapham, D.E. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 291, 1043–1047 (2001).
Nadler, M.J. et al. LTRPC7 is a Mg-ATP–regulated divalent cation channel required for cell viability. Nature 411, 590–595 (2001).
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).
Rodriguez-Soriano, J., Vallo, A. & Garcia-Fuentes, M. Hypomagnesaemia of hereditary renal origin. Pediatr. Nephrol. 1, 465–472 (1987).
Blanchard, A. et al. Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle. Kidney Int. 59, 2206–2215 (2001).
Praga, M. et al. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Kidney Int. 47, 1419–1425 (1995).
Simon, D.B. et al. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285, 103–106 (1999).
Schlingmann, K.P. et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nature Genet. 31,166–170 (2002); advance online publication, 28 May 2002 (DOI: 10.1038/ng889).
Simon, D.B. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet. 12, 24–30 (1996).
Dai, L.J. et al. Magnesium transport in the renal distal convoluted tubule. Physiol. Rev. 81, 51–84 (2001).
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).
Ryazanov, A.G., Pavur, K.S. & Dorovkov, M.V. α-Kinases: a new class of protein kinases with a novel catalytic domain. Curr. Biol. 9, R43–R45 (1999).
Pronicka, E. & Gruszczynska, B. Familial hypomagnesaemia with secondary hypocalcaemia—autosomal or X-linked inheritance? J. Inherit. Metab. Dis. 14, 397–399 (1991).
Ryzen, E., Elbaum, N., Singer, F.R. & Rude, R.K. Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 4, 137–147 (1985).
al-Ghamdi, S.M., Cameron, E.C. & Sutton, R.A. Magnesium deficiency: pathophysiologic and clinical overview. Am. J. Kidney Dis. 24, 737–752 (1994).
Stapleton, F.B. & Nash, D.A. A screening test for hyperuricosuria. J. Pediatr. 102, 88–90 (1983).
We thank the individuals with HSH and their families for participating in this study; J. Rodriguez-Soriano for help in designing and interpreting the magnesium loading studies; A. Nalley, K. Bugge and M. Andrews for technical help; and K. Mykytyn and C. Searby for discussions. V.C.S. acknowledges support from the National Institutes of Health. V.C.S. is an associate investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
About this article
Cite this article
Walder, R., Landau, D., Meyer, P. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31, 171–174 (2002). https://doi.org/10.1038/ng901
High-precision isotopic analysis of Mg and Ca in biological samples using multi-collector ICP-mass spectrometry after their sequential chromatographic isolation – Application to the characterization of the body distribution of Mg and Ca isotopes in mice
Analytica Chimica Acta (2020)
American Journal of Physiology-Renal Physiology (2020)
Severe hypomagnesemia with secondary hypocalcaemia (HSH) presenting as recurrent self terminating Torsades de pointes
IHJ Cardiovascular Case Reports (CVCR) (2020)