{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cyclin M2 (CNNM2) is emerging as a critical factor in maintaining magnesium (Mg²⁺) homeostasis in mammals. Predominantly expressed at the basolateral membrane of kidney distal convoluted tubule cells, CNNM2 plays an essential role in renal Mg²⁺ reabsorption by influencing Mg²⁺-sensitive ion currents and mediating rapid Mg²⁺ flux across epithelial cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Structural studies have revealed that its intracellular cystathionine β‐synthase (CBS) domains bind ATP in a Mg²⁺‐dependent manner, and key mutations within these domains disrupt this interaction and impair Mg²⁺ efflux, underscoring the importance of this region for CNNM2 function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Consistent with its role in magnesium regulation, human genetic studies and animal models have demonstrated that mutations or altered expression of CNNM2 result in hypomagnesemia. In affected individuals, such mutations are associated not only with renal Mg²⁺ wasting but also with secondary clinical manifestations including seizures, intellectual disability, and blood pressure dysregulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, CNNM2 variants have been linked to changes in brain structure and may contribute to neuropsychiatric risk, as evidenced by associations with reduced grey matter volume in frontal regions and an altered social cognitive profile in schizophrenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Further functional studies indicate that, in addition to its renal role, CNNM2 may also participate in modulating cellular processes in other tissues. For instance, in the context of sperm physiology, CNNM2 appears to compensate for related magnesium transport proteins to support Ca²⁺ responses and sperm motility, suggesting broader implications for electrolyte balance in diverse cell types."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these data support a model in which CNNM2—through its ATP-binding CBS domains and propensity to form specific protein complexes—functions as a key mediator of Mg²⁺ homeostasis with important downstream effects on renal, neurological, and cardiovascular physiology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tamra E Meyer, Germaine C Verwoert, Shih-Jen Hwang, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2011.02.005"}], "href": "https://doi.org/10.1016/j.ajhg.2011.02.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21397062"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21397062"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jeroen H F de Baaij, Marchel Stuiver, Iwan C Meij, et al. 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