Intrinsic factor

Gastric intrinsic factor (vitamin B synthesis)
Rendering based on PDB 2CKT.
Available structures PDB 2CKT, 2PMV, 3KQ4
Identifiers
Symbols	GIF; IF; IFMH; INF; TCN3
External IDs	OMIM: 609342 MGI: 1202394 HomoloGene: 3773 GeneCards: GIF Gene
Gene Ontology Molecular function • cobalamin binding Cellular component • extracellular region • extracellular space • endosome • microvillus • apical plasma membrane Biological process • ion transport • cobalt ion transport • cobalamin metabolic process • cobalamin transport Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2694	14603
Ensembl	ENSG00000134812	ENSMUSG00000024682
UniProt	P27352	P52787
RefSeq (mRNA)	NM_005142	NM_008118.3
RefSeq (protein)	NP_005133	NP_032144.2
Location (UCSC)	Chr 11: 59.6 – 59.61 Mb	Chr 19: 11.82 – 11.84 Mb
PubMed search	[1]	[2]

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.

Treatment

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, as of yet, no standards have been set for treatment by the sublingual route and injections of B₁₂ are the only reliable method of treatment.

Model organisms

Gif knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Homozygous Fertility	Abnormal
General Observations	Abnormal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Tail epidermis wholemount	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
MicroCT & Quantitative Faxitron	Normal
Salmonella infection	Abnormal
Citrobacter infection	Abnormal
All tests and analysis from

Model organisms have been used in the study of intrinsic factor function. A conditional knockout mouse line, called Gif^{tm1a(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.

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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1167747. 
• 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 Río E, Sardà 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2636683. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2077253. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=528928. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=554821. 
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• 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. 

External links

• MeSH Intrinsic+factor
• MedlinePlus Encyclopedia 002381
• Overview at colostate.edu