Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500HB, Nijmegen, The Netherlands.
Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Sci Rep. 2021 Apr 15;11(1):8217. doi: 10.1038/s41598-021-87548-6.
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 Mg reabsorption. Here, we used a Cnnm2 knock out mouse model, generated by CRISPR/Cas9 technology, to assess the role of CNNM2 in Mg 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 Mg concentration compared to wildtype littermates. Subsequently, adult Cnnm2 mice were fed with low, control, or high Mg diets for two weeks. Adult Cnnm2 mice showed mild hypomagnesaemia compared to Cnnm2 mice and increased serum Ca levels, independent of dietary Mg intake. Faecal analysis displayed increased Mg and Ca 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 Mg homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg deficiency in mice and patients.
患有细胞周期蛋白 M2（Cyclin M2，CNNM2）突变的患者会出现低镁血症、癫痫发作和智力障碍。尽管 CNNM2 的分子功能仍存在争议，但该蛋白被认为对肾脏镁重吸收至关重要。在这里，我们使用 CRISPR/Cas9 技术生成的 Cnnm2 敲除小鼠模型来评估 CNNM2 在镁稳态中的作用。繁殖 Cnnm2 小鼠导致在胚胎第 18 天呈孟德尔分布。然而，仅有 4 只 Cnnm2 幼崽存活。与野生型同窝仔相比，Cnnm2 幼崽的血清镁浓度明显较低。随后，成年 Cnnm2 小鼠在两周内分别喂食低镁、对照或高镁饮食。与 Cnnm2 小鼠相比，成年 Cnnm2 小鼠表现出轻度低镁血症，并增加了血清 Ca 水平，这与饮食镁摄入无关。粪便分析显示 Cnnm2 小鼠的 Mg 和 Ca 排泄增加。肾脏和结肠中 Trpm6、Trpm7 和 Slc41a1 的转录谱分析未显示基于基因型的影响。股骨的 microCT 分析显示骨骼形态和密度相等。总之，CNNM2 对胚胎发育和镁稳态至关重要。我们的数据表明 CNNM2 在肠道中具有以前未描述的作用，这可能导致小鼠和患者的镁缺乏。
