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

Abstract 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...

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Autores principales:	Gijs A. C. Franken, Murat Seker, Caro Bos, Laura A. H. Siemons, Bram C. J. van der Eerden, Annabel Christ, Joost G. J. Hoenderop, René J. M. Bindels, Dominik Müller, Tilman Breiderhoff, Jeroen H. F. de Baaij
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/425e0fafae4846bc82edea83d0b50985
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spelling	oai:doaj.org-article:425e0fafae4846bc82edea83d0b509852021-12-02T18:03:46ZCyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects10.1038/s41598-021-87548-62045-2322https://doaj.org/article/425e0fafae4846bc82edea83d0b509852021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87548-6https://doaj.org/toc/2045-2322Abstract 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.Gijs A. C. FrankenMurat SekerCaro BosLaura A. H. SiemonsBram C. J. van der EerdenAnnabel ChristJoost G. J. HoenderopRené J. M. BindelsDominik MüllerTilman BreiderhoffJeroen H. F. de BaaijNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gijs A. C. Franken Murat Seker Caro Bos Laura A. H. Siemons Bram C. J. van der Eerden Annabel Christ Joost G. J. Hoenderop René J. M. Bindels Dominik Müller Tilman Breiderhoff Jeroen H. F. de Baaij Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
description	Abstract 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.
format	article
author	Gijs A. C. Franken Murat Seker Caro Bos Laura A. H. Siemons Bram C. J. van der Eerden Annabel Christ Joost G. J. Hoenderop René J. M. Bindels Dominik Müller Tilman Breiderhoff Jeroen H. F. de Baaij
author_facet	Gijs A. C. Franken Murat Seker Caro Bos Laura A. H. Siemons Bram C. J. van der Eerden Annabel Christ Joost G. J. Hoenderop René J. M. Bindels Dominik Müller Tilman Breiderhoff Jeroen H. F. de Baaij
author_sort	Gijs A. C. Franken
title	Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
title_short	Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
title_full	Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
title_fullStr	Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
title_full_unstemmed	Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects
title_sort	cyclin m2 (cnnm2) knockout mice show mild hypomagnesaemia and developmental defects
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/425e0fafae4846bc82edea83d0b50985
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Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects

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