{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CNNM4 is a member of the ancient conserved domain protein (ACDP)/cyclin M family that functions primarily as a magnesium (Mg2+) transporter. Genetic studies have associated common variation in CNNM4 with serum magnesium concentrations, highlighting its role in systemic Mg2+ homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In polarized epithelial cells, CNNM4 localizes to the basolateral membrane and mediates Mg2+ extrusion—exchanging intracellular Mg2+ for extracellular Na+—a process critical for intestinal Mg2+ absorption and enamel formation by ameloblasts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Loss-of-function mutations in CNNM4 are the molecular basis of Jalili syndrome, a recessively inherited disorder characterized by a combination of cone-rod dystrophy and amelogenesis imperfecta. These clinical manifestations reflect defective Mg2+ transport in both retinal cells and dental tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in regulating extracellular magnesium, CNNM4-dependent Mg2+ efflux influences intracellular energy metabolism and cellular signaling pathways. For instance, CNNM4 modulates AMPK/mTOR signaling and thereby impacts tumor progression, as reduced Mg2+ efflux is associated with enhanced cancer cell growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, CNNM4 is required for proper Ca2+ influx during sperm capacitation, and its deficiency leads to compromised sperm motility and abnormal Ca2+ responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structure–function studies have revealed that the conserved cystathionine-β-synthase (CBS) domains within CNNM4 are essential for its Mg2+ transport activity, mediating interactions with adenosine triphosphate in a Mg2+-dependent manner."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, proper basolateral sorting of CNNM4 in epithelial cells is achieved via complementary interactions with clathrin adaptor protein complexes AP‑1A and AP‑1B"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while CNNM4 also forms part of a regulatory complex with the TRPM7 channel to stimulate divalent cation influx in a TRPM7-dependent manner."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore CNNM4’s multifaceted role in Mg2+ homeostasis, linking its transporter function to diverse physiological processes including mineral metabolism, retinal function, sperm physiology, and energy metabolism, while its disruption causes clinically significant disorders such as Jalili syndrome.\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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