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Although the molecular function of CNNM2 is under debate, the protein is considered essential for renal Mg<jats:sup>2+<\/jats:sup> reabsorption. Here, we used a <jats:italic>Cnnm2<\/jats:italic> knock out mouse model, generated by CRISPR\/Cas9 technology, to assess the role of CNNM2 in Mg<jats:sup>2+<\/jats:sup> homeostasis. Breeding <jats:italic>Cnnm2<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only four <jats:italic>Cnnm2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> pups were born alive. The <jats:italic>Cnnm2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> pups had a significantly lower serum Mg<jats:sup>2+<\/jats:sup> concentration compared to wildtype littermates. Subsequently, adult <jats:italic>Cnnm2<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice were fed with low, control, or high Mg<jats:sup>2+<\/jats:sup> diets for two weeks. Adult <jats:italic>Cnnm2<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice showed mild hypomagnesaemia compared to <jats:italic>Cnnm2<\/jats:italic><jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> mice and increased serum Ca<jats:sup>2+<\/jats:sup> levels, independent of dietary Mg<jats:sup>2+<\/jats:sup> intake. Faecal analysis displayed increased Mg<jats:sup>2+<\/jats:sup> and Ca<jats:sup>2+<\/jats:sup> excretion in the <jats:italic>Cnnm2<\/jats:italic><jats:sup>+<jats:italic>\/\u2212<\/jats:italic><\/jats:sup> mice. Transcriptional profiling of <jats:italic>Trpm6<\/jats:italic>, <jats:italic>Trpm7<\/jats:italic>, and <jats:italic>Slc41a1<\/jats:italic> in 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 Mg<jats:sup>2+<\/jats:sup> homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg<jats:sup>2+<\/jats:sup> deficiency in mice and patients.<\/jats:p>","DOI":"10.1038\/s41598-021-87548-6","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T10:18:05Z","timestamp":1618481885000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects"],"prefix":"10.1038","volume":"11","author":[{"given":"Gijs A. 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