Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia


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.

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Figure 1: Intron–exon structure of TRPM6.
Figure 2: Pedigrees and mutational analysis of the consanguineous families and the one nonconsanguineous family affected with HSH.
Figure 3: TRPM6 expression in human and mouse tissues.
Figure 4: Urinary excretion of magnesium during infusion of magnesium sulfate in six individuals with HSH is plotted against the ultrafiltered (UF) magnesium load (y = 0.06x3.07, R2 = 0.6465).
Figure 5

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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.

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Correspondence to Val C. Sheffield.

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Walder, R., Landau, D., Meyer, P. et al. Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 31, 171–174 (2002).

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