Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects

Abstract

AbstractPatients with mutations in Cyclin M2 (CNNM2) suffer from hypomagnesaemia, seizures, and intellectual disability. Although the molecular function of CNNM2 is under debate, the protein is considered essential for renal Mg2+reabsorption. Here, we used aCnnm2knock out mouse model, generated by CRISPR/Cas9 technology, to assess the role of CNNM2 in Mg2+homeostasis. BreedingCnnm2+/−mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only fourCnnm2−/−pups were born alive. TheCnnm2−/−pups had a significantly lower serum Mg2+concentration compared to wildtype littermates. Subsequently, adultCnnm2+/−mice were fed with low, control, or high Mg2+diets for two weeks. AdultCnnm2+/−mice showed mild hypomagnesaemia compared toCnnm2+/+mice and increased serum Ca2+levels, independent of dietary Mg2+intake. Faecal analysis displayed increased Mg2+and Ca2+excretion in theCnnm2+/−mice. Transcriptional profiling ofTrpm6,Trpm7, andSlc41a1in kidneys and colon did not reveal effects based on genotype. Microcomputed tomography analysis of the femurs demonstrated equal bone morphology and density. In conclusion, CNNM2 is vital for embryonic development and Mg2+homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg2+deficiency in mice and patients.