{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTranscobalamin II (TCN2) is a key vitamin B₁₂ transport protein that mediates the delivery of cobalamin to cells, thereby supporting essential one‐carbon metabolism processes such as DNA synthesis, methylation reactions, and homocysteine clearance. Functional genetic variations in TCN2—for example, the well‐studied 776C>G (p.Pro259Arg) polymorphism—have been shown to alter its binding affinity for vitamin B₁₂ and affect circulating levels of its active complex (holotranscobalamin), which in turn influences intracellular vitamin B₁₂ availability. Such differences have been associated with altered biomarker profiles and, ultimately, with various clinical phenotypes ranging from neurodevelopmental and spontaneous abortion outcomes to age‐related vitamin B₁₂ deficiency."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its fundamental role in normal physiology, altered TCN2 function—mediated by its genetic variants—has been implicated in a spectrum of disease processes. Variants such as TCN2 776C>G have been linked to disruptions in vitamin B₁₂ bioavailability, as evidenced by changes in holotranscobalamin, methylmalonic acid, and homocysteine levels. These metabolic disturbances have been observed in studies of neural tube defects, orofacial clefts, congenital heart anomalies, and certain cancers (including altered CpG island methylation in colorectal tumors), underscoring the potential pathogenic impact of impaired vitamin B₁₂ transport on embryonic development and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional population‐based and mechanistic studies have further extended the significance of TCN2 by demonstrating its involvement not only in vitamin B₁₂ status and related metabolic markers but also in modifying clinical outcomes in diverse settings such as frailty, stroke, and even cancer cell adaptation under hypoxic conditions. Downregulation of TCN2 under hypoxia, for instance, has been linked to a mesenchymal and cancer stem cell phenotype, while meta‐analyses reveal that specific TCN2 polymorphisms impact holotranscobalamin and homocysteine concentrations. Such findings support the notion that genetic variability in TCN2 can influence susceptibility to complex conditions—including hypertension, inflammatory disorders, and congenital malformations—by modulating vitamin B₁₂ trafficking and one‐carbon metabolism."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Joshua W Miller, Marisa I Ramos, Marjorie G Garrod, et al. 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