|Gastric intrinsic factor (vitamin B synthesis)|
Rendering based on PDB .
Intrinsic factor (IF) also known as gastric intrinsic factor (GIF) is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine. In humans, the gastric intrinsic factor protein is encoded by the GIF gene.
Upon entry into the stomach, vitamin B12 becomes bound to haptocorrin (R factor), a glycoprotein. The resulting complex enters the duodenum, where pancreatic enzymes digest haptocorrin. In the less acidic environment of the small intestine, B12 can then bind to intrinsic factor. This new complex travels to the ileum, where special epithelial cells endocytose them. Inside the cell, B12 dissociates once again and binds to another protein, transcobalamin II. The new complex can exit the epithelial cells to enter the liver.
Site of secretion 
The intrinsic factor is secreted by the stomach. It is present in the gastric juice as well as in the gastric mucous membrane. The optimum pH for its action is 7 and it is inactivated at temperatures above 45 °C. It does not necessarily run parallel with the amount of HCl or pepsin in the gastric juice. So in some cases, the intrinsic factor may be present even if there is no HCl or pepsin or vice versa. The site of formation of the intrinsic factor varies in different species. In pigs it is obtained from the pylorus and beginning of the duodenum. In human beings it is present in the fundus and body of the stomach.
Clinical significance 
In pernicious anemia, an autoimmune disease, autoantibodies directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, malabsorption of vitamin B12, and subsequent megaloblastic anemia. Atrophic gastritis can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall. Pancreatic exocrine insufficiency can interfere with normal dissociation of vitamin B12 from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.
Bariatric surgery is a known risk factor in the development of pernicious anemia. Other risk factors contributing to this condition are stomach tumors, gastric ulcers, and excessive consumption of alcohol.
Patients experiencing an insufficiency in their intrinsic factor levels cannot benefit from a low dose oral vitamin B12 supplement, because it will not absorb through the wall of the small intestine. Historically, the disease was thought untreatable before the discovery that it could be managed with regular injections of vitamin B12, thus bypassing the digestive tract. More recently, Swedish researchers discovered that sufficiently large doses of B12 can also be absorbed sublingually, removing the necessity for injectable B12. However, no standards have been set for treatment by the sublingual route yet, and injections of B12 are the only reliable method of treatment.
Model organisms 
|Glucose tolerance test||Normal|
|Auditory brainstem response||Normal|
|Peripheral blood lymphocytes||Normal|
|Tail epidermis wholemount||Normal|
|MicroCT & Quantitative Faxitron||Normal|
|All tests and analysis from|
Model organisms have been used in the study of intrinsic factor function. A conditional knockout mouse line, called Giftm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty-seven tests were carried out on mutant mice and four significant abnormalities were observed. Homozygous mutant males displayed increased aggression towards their pups and therefore had reduced fecundity. Mutants of both sex had increased susceptibility to infection with both Citrobacter and Salmonella.
- Hewitt JE, Gordon MM, Taggart RT, Mohandas TK, Alpers DH (June 1991). "Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11". Genomics 10 (2): 432–40. doi:10.1016/0888-7543(91)90329-D. PMID 2071148.
- AU - Berlin H, Berlin R, Brante G (1968). "ORAL TREATMENT OF PERNICIOUS ANEMIA WITH HIGH DOSES OF VITAMIN B12 WITHOUT INTRINSIC FACTOR". Acta Medica Scandinavica 184 (1-6): 247–258. doi:10.1111/j.0954-6820.1968.tb02452.x.
- "Citrobacter infection data for Gif". Wellcome Trust Sanger Institute.
- Gerdin AK (2010). The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice. Acta Opthalmologica 88: 925-7.: Wiley. doi:10.1111/j.1755-3768.2010.4142.x.
- Mouse Resources Portal, Wellcome Trust Sanger Institute.
- "International Knockout Mouse Consortium".
- "Mouse Genome Informatics".
- Skarnes Wc, R. B.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M. et al. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–342. doi:10.1038/nature10163. PMID 21677750.
- Dolgin E (June 2011). "Mouse library set to be knockout". Nature 474: 262–263. doi:10.1038/474262a. PMID 21677718.
- Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism.". Genome Biol 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
Further reading 
- Howard TA, Misra DN, Grove M, et al. (1996). "Human gastric intrinsic factor expression is not restricted to parietal cells". J. Anat. 189 (Pt 2): 303–13. PMC 1167747. PMID 8886952.
- Kozyraki R, Kristiansen M, Silahtaroglu A, et al. (1998). "The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region". Blood 91 (10): 3593–600. PMID 9572993.
- Wahlstedt V, Gräsbeck R (1985). "Cobalamin-binding proteins in human urine: identification and quantitation". J. Lab. Clin. Med. 106 (4): 439–46. PMID 4045300.
- Remacha AF, Del RÃo E, SardÃ MP, et al. (2008). "Role of (Glu --> Arg, Q5R) mutation of the intrinsic factor in pernicious anemia and other causes of low vitamin B12". Ann. Hematol. 87 (7): 599–600. doi:10.1007/s00277-008-0465-0. PMID 18338170.
- Ament AE, Li Z, Sturm AC, et al. (2009). "Juvenile cobalamin deficiency in individuals of African ancestry is caused by a founder mutation in the intrinsic factor gene GIF". Br. J. Haematol. 144 (4): 622–4. doi:10.1111/j.1365-2141.2008.07496.x. PMC 2636683. PMID 19036097.
- Mathews FS, Gordon MM, Chen Z, et al. (2007). "Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution". Proc. Natl. Acad. Sci. U.S.A. 104 (44): 17311–6. doi:10.1073/pnas.0703228104. PMC 2077253. PMID 17954916.
- Fedosov SN, Fedosova NU, Berglund L, et al. (2005). "Composite organization of the cobalamin binding and cubilin recognition sites of intrinsic factor". Biochemistry 44 (9): 3604–14. doi:10.1021/bi047936v. PMID 15736970.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Tanner SM, Li Z, Perko JD, et al. (2005). "Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene". Proc. Natl. Acad. Sci. U.S.A. 102 (11): 4130–3. doi:10.1073/pnas.0500517102. PMC 554821. PMID 15738392.
- Yassin F, Rothenberg SP, Rao S, et al. (2004). "Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency". Blood 103 (4): 1515–7. doi:10.1182/blood-2003-07-2239. PMID 14576042.
- Gordon MM, Brada N, Remacha A, et al. (2004). "A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency". Hum. Mutat. 23 (1): 85–91. doi:10.1002/humu.10297. PMID 14695536.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Andersen CB, Madsen M, Storm T, et al. (2010). "Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes". Nature 464 (7287): 445–8. doi:10.1038/nature08874. PMID 20237569.
- Katz M, Lee SK, Cooper BA (1972). "Vitamin B 12 malabsorption due to a biologically inert intrinsic factor". N. Engl. J. Med. 287 (9): 425–9. doi:10.1056/NEJM197208312870902. PMID 5044916.
- Yazaki Y, Chow G, Mattie M (November 2006). "A single-center, double-blinded, randomized controlled study to evaluate the relative efficacy of sublingual and oral vitamin B-complex administration in reducing total serum homocysteine levels". J Altern Complement Med 12 (9): 881–5. doi:10.1089/acm.2006.12.881. PMID 17109579.
- Intrinsic factor at the US National Library of Medicine Medical Subject Headings (MeSH)
- MedlinePlus Encyclopedia 002381
- Overview at colostate.edu