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

G A C Franken, M Seker, C van den Bos, L A H Siemons, Bram van der Eerden, A Christ, JGJ Hoenderop, RJM Bindels, D Müller, T Breiderhoff, JHF de Baaij*

*Corresponding author for this work

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Patients 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 a Cnnm2 knock out mouse model, generated by CRISPR/Cas9 technology, to assess the role of CNNM2 in Mg2+ homeostasis. Breeding Cnnm2+/? mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only four Cnnm2?/? pups were born alive. The Cnnm2?/? pups had a significantly lower serum Mg2+ concentration compared to wildtype littermates. Subsequently, adult Cnnm2+/? mice were fed with low, control, or high Mg2+ diets for two weeks. Adult Cnnm2+/? mice showed mild hypomagnesaemia compared to Cnnm2+/+ mice and increased serum Ca2+ levels, independent of dietary Mg2+ intake. Faecal analysis displayed increased Mg2+ and Ca2+ excretion in the Cnnm2+/? mice. Transcriptional profiling of Trpm6, Trpm7, and Slc41a1 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 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.
Original languageEnglish
Article number8217
JournalSci. Rep.
Issue number1
Publication statusPublished - 15 Apr 2021

Bibliographical note

Funding Information:
This work was financially supported by grants from the Netherlands Organization for Scientific Research (NWO Veni 016.186.012. Vici 016.130.668), and the European Joint Program for Rare Diseases (EJPRD2019-40). M.S. and D.M. were supported by the Deutsche Forschungsgemeinschaft (DFG), Research Training Group GRK 2318.

Publisher Copyright:
© 2021, The Author(s).

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