CNNM2, also known as Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2, is closely related to magnesium (Mg2+) homeostasis. It is primarily expressed in the brain and the distal convoluted tubule (DCT) of the kidney. In the kidney, it is involved in the basolateral Mg2+ extrusion in DCT, which is crucial for maintaining normal serum Mg2+ levels. Abnormalities in CNNM2 are associated with hypomagnesemia, and it may also play a role in the pathogenesis of intracranial aneurysms and schizophrenia [1,2,3].

In CNNM2 knockout mouse models, Cnnm2-/- pups had significantly lower serum Mg2+ concentration compared to wildtype littermates. Adult Cnnm2+/- mice showed mild hypomagnesaemia and increased serum Ca2+ levels, along with increased Mg2+ and Ca2+ excretion in faeces. This indicates CNNM2 is vital for embryonic development and Mg2+ homeostasis, and may have an unreported role in the intestine [4]. In zebrafish knockdown models of cnnm2, there were disturbed brain development, neurodevelopmental impairments, and reduced body Mg content, phenotypes rescued by wild-type Cnnm2 cRNA injection but not by mutant cRNA, suggesting CNNM2 is fundamental for brain development, neurological functioning and Mg2+ homeostasis [5].

In conclusion, CNNM2 is essential for maintaining Mg2+ homeostasis, which is crucial for normal embryonic development, brain development, and neurological function. Studies using gene knockout models in mice and zebrafish have significantly contributed to understanding its role in these processes, as well as its association with diseases such as hypomagnesemia-related disorders.

References:

1. Tseng, Min-Hua, Yang, Sung-Sen, Sung, Chih-Chien, Chu, Shih-Ming, Lin, Shih-Hua. 2022. Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure. In Frontiers in genetics, 13, 875013. doi:10.3389/fgene.2022.875013. https://pubmed.ncbi.nlm.nih.gov/35846113/

2. Bakker, Mark K, van Straten, Tijmen, Chong, Michael, Gill, Dipender, Ruigrok, Ynte M. 2022. Anti-Epileptic Drug Target Perturbation and Intracranial Aneurysm Risk: Mendelian Randomization and Colocalization Study. In Stroke, 54, 208-216. doi:10.1161/STROKEAHA.122.040598. https://pubmed.ncbi.nlm.nih.gov/36300369/

3. Zhou, Dan-Yang, Su, Xi, Wu, Yong, Li, Ming, Song, Meng. 2023. Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia. In Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 49, 433-442. doi:10.1038/s41386-023-01732-y. https://pubmed.ncbi.nlm.nih.gov/37715107/

4. Franken, Gijs A C, Seker, Murat, Bos, Caro, Breiderhoff, Tilman, de Baaij, Jeroen H F. 2021. Cyclin M2 (CNNM2) knockout mice show mild hypomagnesaemia and developmental defects. In Scientific reports, 11, 8217. doi:10.1038/s41598-021-87548-6. https://pubmed.ncbi.nlm.nih.gov/33859252/

5. Arjona, Francisco J, de Baaij, Jeroen H F, Schlingmann, Karl P, Bindels, René J M, Hoenderop, Joost G J. 2014. CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. In PLoS genetics, 10, e1004267. doi:10.1371/journal.pgen.1004267. https://pubmed.ncbi.nlm.nih.gov/24699222/