{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMethylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one‐carbon metabolism that catalyzes the irreversible conversion of 5,10‑methylenetetrahydrofolate to 5‑methyltetrahydrofolate. This reaction is vital because 5‑methylTHF provides the methyl group required for remethylating homocysteine to methionine, thereby supplying S‑adenosylmethionine—the universal methyl donor for DNA methylation, protein methylation, and many other essential biochemical processes. In short, MTHFR’s function underpins proper DNA synthesis, repair, and epigenetic regulation by maintaining an optimal pool of methyl groups."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCommon polymorphisms in the MTHFR gene—most notably C677T and A1298C—lead to reduced enzyme activity or altered thermostability. These genetic variants diminish the conversion efficiency to 5‑methylTHF, often resulting in elevated circulating homocysteine and a perturbed folate balance. As a consequence, carriers of these variants have been linked in numerous studies to altered risks for neural tube defects, cardiovascular and cerebrovascular disorders, several forms of cancer, and neuropsychiatric conditions. The resulting imbalance in folate and methyl group availability highlights the importance of MTHFR genotype as a modifier in diverse clinical and developmental outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central metabolic role, MTHFR’s regulation of methyl donor availability has broader implications for epigenetic control and cellular health. Altered MTHFR activity not only affects DNA methylation patterns and chromatin stability but also influences the response to therapeutic interventions—for example, modulating methotrexate efficacy and toxicity in rheumatoid arthritis—as well as the risk of neurodegenerative and thrombotic disorders. These diverse findings, spanning investigations into Alzheimer disease, stroke, cancer subtypes, and even behavioral conditions, underscore the enzyme’s pivotal role at the intersection of nutrition, genetics, and environmental exposures."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "L D Botto, Q Yang "}, {"type": "b", "children": [{"type": "t", "text": "5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Epidemiol (2000)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/oxfordjournals.aje.a010290"}], "href": "https://doi.org/10.1093/oxfordjournals.aje.a010290"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10791559"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10791559"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Simonetta Friso, Sang-Woon Choi, Domenico Girelli, et al. 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