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Transient receptor potential melastatin 6 knockout mice are lethal whereas heterozygous deletion results in mild
Titia E Woudenberg-Vrenken1, Arjaree Sukinta, Annemiete W van der Kemp
1Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Background:
Hypomagnesemia with secondary hypocalcemia is due to disturbed renal and intestinal magnesium (Mg(2+)) (re)absorption. The underlying defect is a mutation in the transient receptor potential melastatin type 6 (TRPM6), a Mg(2+)-permeable ion channel expressed in the kidney and intestine. Our aim was to characterize homozygous (-/-) and heterozygous (+/-) TRPM6 knockout mice with respect to Mg(2+) homeostasis.
Methods:
TRPM6(+/-) mice were bred on a normal (0.19% wt/wt Mg(2+)) and high (0.48% wt/wt Mg(2+)) Mg(2+) diet. In the offspring, 24-hour urinary Mg(2+) 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% Mg(2+) diet. In TRPM6(+/-) mice on both diets, serum Mg(2+) levels were significantly lower, and renal and intestinal TRPM6 mRNA expression was reduced. Urinary Mg(2+) excretion was unaffected.
Conclusions:
Homozygous TRPM6 deletion is embryonic lethal in mice. Heterozygous deletion of TRPM6 results in a mild hypomagnesemia. The Mg(2+)-enriched diet could not compensate for either embryonic lethality or hypomagnesemia caused by TRPM6 deficiency.
Insights
Homozygous TRPM6 gene deletion is lethal in mice. Heterozygous TRPM6 deficiency causes mild hypomagnesemia, which a high magnesium diet cannot fix.
Area of Science:
- Genetics
- Physiology
- Molecular Biology
Background:
- Hypomagnesemia with secondary hypocalcemia stems from impaired renal and intestinal magnesium (Mg2+) reabsorption.
- A mutation in the transient receptor potential melastatin type 6 (TRPM6) ion channel underlies this condition.
- TRPM6 is crucial for Mg2+ permeability and is expressed in the kidney and intestine.
Purpose of the Study:
- To investigate magnesium (Mg2+) homeostasis in homozygous (-/-) and heterozygous (+/-) TRPM6 knockout mice.
- To understand the role of TRPM6 in Mg2+ absorption and overall mineral balance.
- To assess the impact of a high Mg2+ diet on TRPM6 deficiency.
Main Methods:
- TRPM6(+/-) mice were bred and maintained on normal and high Mg2+ diets.
- Offspring underwent analysis of 24-hour urinary Mg2+ and calcium excretion.
- Serum Mg2+ and calcium concentrations were measured, alongside TRPM6 mRNA expression in the kidney and colon.
Main Results:
- No homozygous TRPM6(-/-) offspring were observed, indicating embryonic lethality.
- TRPM6(+/-) mice exhibited significantly lower serum Mg2+ levels on both diets.
- Reduced renal and intestinal TRPM6 mRNA expression was noted in TRPM6(+/-) mice, with unaffected urinary Mg2+ excretion.
Conclusions:
- Complete TRPM6 deletion is embryonically lethal in mice.
- Partial TRPM6 deficiency leads to mild hypomagnesemia.
- Elevated dietary Mg2+ does not rescue embryonic lethality or correct hypomagnesemia in TRPM6-deficient mice.
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