CNNM2, also known as Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2, is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney. It is involved in magnesium (Mg²⁺) homeostasis, with a role in basolateral Mg²⁺ extrusion in the DCT [2]. Mutations in CNNM2 have been linked to hypomagnesemia, seizure, and intellectual disability (HSMR) syndrome, highlighting its importance in maintaining normal physiological function [1].

In a Cnnm2 knockout mouse model, Cnnm2⁻/⁻ pups had significantly lower serum Mg²⁺ concentration compared to wildtype littermates, and adult Cnnm2⁺/⁻ mice showed mild hypomagnesaemia, increased serum Ca²⁺ levels, and increased Mg²⁺ and Ca²⁺ excretion in faeces. This indicates CNNM2 is vital for embryonic development and Mg²⁺ homeostasis, and may have a previously undescribed role in the intestine [3]. In zebrafish, knockdown of cnnm2 isoforms resulted in disturbed brain development, neurodevelopmental impairments, and reduced body Mg content, rescued by wild-type Cnnm2 cRNA but not mutant cRNA, suggesting CNNM2 is fundamental for brain development, neurological functioning and Mg²⁺ homeostasis [4].

In conclusion, CNNM2 plays a crucial role in Mg²⁺ homeostasis, embryonic development, brain development, and neurological functioning. The study of Cnnm2 knockout mouse models and zebrafish knockdown models has provided valuable insights into the gene's function in these processes, and into the pathogenesis of diseases such as hypomagnesemia, epilepsy, and intellectual disability associated with CNNM2 mutations.