Transient receptor potential melastatin 6 knockout mice are lethal whereas heterozygous deletion results in mild hypomagnesemia.
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.
Woudenberg-Vrenken
Titia E
TE
Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Sukinta
Arjaree
A
van der Kemp
Annemiete W
AW
Bindels
René J M
RJ
Hoenderop
Joost G J
JG
D000818:Animals; D002118:Calcium / Q000652:urine; D005243:Feces / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D005804:Genes, Lethal; D005838:Genotype; D006579:Heterozygote; D008274:Magnesium / Q000097:blood / Q000652:urine; D008275:Magnesium Deficiency / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index; D050053:TRPM Cation Channels / Q000235:genetics* / Q000378:metabolism
D050053:TRPM Cation Channels; C530168:Trpm6 protein, mouse; D008274:Magnesium; D002118:Calcium