Background: Hypomagnesemia with secondary hypocalcemia is due to disturbed renal and intestinal magnesium (Mg2+) (re)absorption. The underlying defect is a mutation in the transient receptor potential melastatin type 6 (TRPM6), a Mg2+-permeable ion channel expressed in the kidney and intestine. Our aim was to characterize homozygous (–/–) and heterozygous (+/–) TRPM6 knockout mice with respect to Mg2+ homeostasis. Methods: TRPM6+/– mice were bred on a normal (0.19% wt/wt Mg2+) and high (0.48% wt/wt Mg2+) Mg2+ diet. In the offspring, 24-hour urinary Mg2+ and calcium excretion as well as serum concentrations of both were determined. TRPM6 mRNA expression in the kidney and colon was measured. Results: On the regular diet, 30% of the offspring were TRPM6 wild-type (+/+), 70% were TRPM6+/–, and none were TRPM6–/–. The genotypic distribution of the litters remained the same on the 0.48% Mg2+ diet. In TRPM6+/– mice on both diets, serum Mg2+ levels were significantly lower, and renal and intestinal TRPM6 mRNA expression was reduced. Urinary Mg2+ excretion was unaffected. Conclusions: Homozygous TRPM6 deletion is embryonic lethal in mice. Heterozygous deletion of TRPM6 results in a mild hypomagnesemia. The Mg2+-enriched diet could not compensate for either embryonic lethality or hypomagnesemia caused by TRPM6 deficiency.

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