{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Gastric intrinsic factor (GIF), sometimes referred to in the context of cobalamin‐binding intrinsic factor (CBLIF), is a glycoprotein secreted primarily by the stomach’s parietal cells that plays an essential role in the absorption of vitamin B12 (cobalamin) from the gastrointestinal tract. In the acidic gastric environment, GIF binds dietary cobalamin, thereby protecting it from degradation and enabling its subsequent uptake in the distal ileum via a receptor complex formed by cubilin and amnionless."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural studies have revealed that GIF interacts with cobalamin and the binding domains of cubilin in a calcium‐dependent manner, thus facilitating a tightly regulated ligand–receptor coupling mechanism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Genetic and molecular studies have demonstrated that mutations in the GIF gene result in congenital intrinsic factor deficiency, leading to malabsorption of vitamin B12, megaloblastic anemia, and neurological abnormalities."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "6"}]}, {"type": "t", "text": " In addition, genome‐wide and clinical studies have linked variations in GIF – along with other factors such as FUT2 – to altered vitamin B12 status, which may predispose to conditions as diverse as neural tube defects and pernicious anemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Furthermore, transcriptome analyses in certain gastric lesions have shown profound down‐regulation of GIF expression, emphasizing its role in gastrointestinal physiology and its potential contribution to disease when misregulated."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Finally, comprehensive reviews of autoimmune gastritis and pernicious anemia have underscored the historical and clinical importance of GIF in ensuring efficient cobalamin uptake and protecting against vitamin B12 deficiency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christian Brix Folsted Andersen, Mette Madsen, Tina Storm, et al. 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