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Alpha-fetoprotein (AFP, α-fetoprotein; also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or alpha fetal protein) is a protein that in humans is encoded by the AFP gene. The AFP gene is located on the q arm of chromosome 4 (4q25).
AFP is a major plasma protein produced by the yolk sac and the liver during fetal development. It is thought to be the fetal form of serum albumin. AFP binds to copper, nickel, fatty acids and bilirubin and is found in monomeric, dimeric and trimeric forms.
Structure[edit | edit source]
Function[edit | edit source]
AFP is the most abundant plasma protein found in the human fetus. Plasma levels decrease rapidly after birth but begin decreasing prenatally starting at the end of the first trimester. Normal adult levels are usually achieved by the age of 8 to 12 months. The function of AFP in adults is unknown; however, in rodent fetuses it binds estradiol to prevent the transport of this hormone across the placenta. The main function of this is to prevent the masculinization of female fetuses. As human AFP does not bind estrogen, its function in human fetuses is less clear.
The rodent AFP system can be overridden with massive injections of estrogen, which swamp the AFP system and will masculinize the fetus. The masculinizing effect of estrogens may seem counter-intuitive since estrogens are critical for the proper development of female secondary characteristics during puberty. However, this is not the case prenatally. Gonadal hormones from the testes, such as testosterone and antimullerian hormone are required to cause development of a phenotypic male. Without these hormones the fetus will develop into a phenotypic female even if genetically XY. Interestingly, the conversion of testosterone into estradiol by aromatase in many tissues may be an important step in masculinization of that tissue. Masculinization of the brain is thought to occur both by conversion of testosterone into estradiol by aromatase, but also by de novo synthesis of estrogens within the brain. Thus, AFP may protect the fetus from maternal estradiol that would otherwise have a masculinizing effect on the fetus, but its exact role is still controversial.
Serum levels[edit | edit source]
- Main article: Elevated alpha-fetoprotein
Maternal[edit | edit source]
In pregnant women, fetal AFP levels can be monitored in urine. AFP is cleared strongly from the kidneys allowing AFP to tend to mirror fetal serum levels. In contrast, maternal serum AFP levels are much lower but continue to rise until about week 32. This is thought to be because the mother is not utilising the AFP, and therefore clears it from her system without issue.
Infants[edit | edit source]
The normal range of AFP for adults and children is variously reported as under 50, under 10, and under 5 ng/mL. At birth, normal infants have AFP levels 4 or more orders of magnitude above this normal range, that decreases to a normal range over the first year of life.
Very high AFP levels may be subject to hooking (see Tumor marker), which results in the level being reported significantly lower than the actual concentration. This is important for analysis of a series of AFP tumor marker tests, e.g. in the context of post-treatment early surveillance of cancer survivors, where the rate of decrease of AFP has diagnostic value.
Clinical significance[edit | edit source]
- Main article: Elevated alpha-fetoprotein
AFP is measured in pregnant women through the analysis of maternal blood or amniotic fluid, as a screening test for a subset of developmental abnormalities. Some of the diseases in which AFP will be elevated in a person are listed below:
- Down Syndrome (decrease)
- Hepatocellular carcinoma/hepatoma: ↑ α-fetoprotein
- Neural tube defects: ↑ α-fetoprotein in amniotic fluid and maternal serum
- Nonseminomatous germ cell tumors
- Yolk sac tumor
- Ataxia telangectasia: Elevation of AFP is used as one factor in the diagnosis of ataxia telangiectasia.
- Tumors: AFP can also be used as a biomarker to detect a subset of tumors in non-pregnant women, men, and children. A level above 500 nanograms/milliliter of AFP in adults can be indicative of hepatocellular carcinoma, germ cell tumors, and metastatic cancers of the liver.
See also[edit | edit source]
References[edit | edit source]
- Tomasi TB (1977). Structure and function of alpha-fetoprotein. Annual review of medicine 28: 453–65.
- Mizejewski GJ (May 2001). Alpha-fetoprotein structure and function: relevance to isoforms, epitopes, and conformational variants. Experimental biology and medicine (Maywood, N.J.) 226 (5): 377–408.
- Harper ME, Dugaiczyk A (July 1983). Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4. American Journal of Human Genetics 35 (4): 565–72.
- Entrez Gene: Alpha-fetoprotein.
- Pucci P, Siciliano R, Malorni A, Marino G, Tecce MF, Ceccarini C, Terrana B (May 1991). Human alpha-fetoprotein primary structure: a mass spectrometric study. Biochemistry 30 (20): 5061–6.
- Seregni E, Botti C, Bombardieri E (1995). Biochemical characteristics and clinical applications of alpha-fetoprotein isoforms. Anticancer Res. 15 (4): 1491–9.
- Carter CS (2002). "Neuroendocrinology of sexual behavior in the female" Becker JB Behavioral Endocrinology, 88–89, Cambridge, Mass: MIT Press.
- Nef S, Parada LF (December 2000). Hormones in male sexual development. Genes Dev. 14 (24): 3075–86.
- Elbrecht A, Smith RG (1992). Aromatase enzyme activity and sex determination in chickens.. Science 255 (5043): 467–70.
- Bakker J, Baum MJ (2008). Role for estradiol in female-typical brain and behavioral sexual differentiation.. Front Neuroendocrinol 29 (1): 1–16.
- Harding CF (2004). Hormonal modulation of singing: hormonal modulation of the songbird brain and singing behavior.. Ann N Y Acad Sci 1016: 524–39.
- Ball D, Rose E, Alpert E (March 1992). Alpha-fetoprotein levels in normal adults. Am. J. Med. Sci. 303 (3): 157–9.
- Sizaret P, Martel N, Tuyns A, Reynaud S (February 1977). Mean alpha-fetoprotein values of 1,333 males over 15 years by age groups. Digestion 15 (2): 97–103.
- Blohm ME, Vesterling-Hörner D, Calaminus G, Göbel U (1998). Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15 (2): 135–42.
- Ohama K, Nagase H, Ogino K, Tsuchida K, Tanaka M, Kubo M, Horita S, Kawakami K, Ohmori M (October 1997). Alpha-fetoprotein (AFP) levels in normal children. Eur J Pediatr Surg 7 (5): 267–9.
- Lee PI, Chang MH, Chen DS, Lee CY (January 1989). Serum alpha-fetoprotein levels in normal infants: a reappraisal of regression analysis and sex difference. J. Pediatr. Gastroenterol. Nutr. 8 (1): 19–25. Cite error: Invalid
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- Blair JI, Carachi R, Gupta R, Sim FG, McAllister EJ, Weston R (April 1987). Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity. Arch. Dis. Child. 62 (4): 362–9.
- Bader D, Riskin A, Vafsi O, Tamir A, Peskin B, Israel N, Merksamer R, Dar H, David M (November 2004). Alpha-fetoprotein in the early neonatal period--a large study and review of the literature. Clin. Chim. Acta 349 (1-2): 15–23.
- Wu JT, Roan Y, Knight JA (1985). "Serum levels of AFP in normal infants: their clinical and physiological significance" Mizejewski GJ, Porter I Alfa-Fetoprotein and Congenital Disorders, 111–122, New York: Academic Press.
- Jassam N, Jones CM, Briscoe T, Horner JH (July 2006). The hook effect: a need for constant vigilance. Ann. Clin. Biochem. 43 (Pt 4): 314–7.
- Szabó M, Veress L, Münnich A, Papp Z (September 1990). [Alpha fetoprotein concentration in the amniotic fluid in normal pregnancy and in pregnancy complicated by fetal anomaly]. Orv Hetil 131 (39): 2139–42.
- Rosen T, D'Alton ME (December 2005). Down syndrome screening in the first and second trimesters: what do the data show?. Semin. Perinatol. 29 (6): 367–75.
- Le, Tao. First Aid for the USMLE Step 1 2013. New York: McGraw-Hill Medical, 2013. Print.
- Bredaki FE, Poon LC, Birdir C, Escalante D, Nicolaides KH (2012). First-trimester screening for neural tube defects using alpha-fetoprotein. Fetal. Diagn. Ther. 31 (2): 109–14.
- Taylor AM, Byrd PJ (October 2005). Molecular pathology of ataxia telangiectasia. J. Clin. Pathol. 58 (10): 1009–15.
- Mesfin FB, Bennett JA, Jacobson HI, Zhu S, Andersen TT (April 2000). Alpha-fetoprotein-derived antiestrotrophic octapeptide. Biochimica et Biophysica Acta 1501 (1): 33–43.
Further reading[edit | edit source]
- Nahon JL (1987). The regulation of albumin and alpha-fetoprotein gene expression in mammals. Biochimie 69 (5): 445–59.
- Tilghman SM (1989). The structure and regulation of the alpha-fetoprotein and albumin genes. Oxf. Surv. Eukaryot. Genes 2: 160–206.
- Mizejewski GJ (2003). Biological role of alpha-fetoprotein in cancer: prospects for anticancer therapy. Expert Rev Anticancer Ther 2 (6): 709–35.
- Yachnin S, Hsu R, Heinrikson RL, Miller JB (1977). Studies on human alpha-fetoprotein. Isolation and characterization of monomeric and polymeric forms and amino-terminal sequence analysis. Biochim. Biophys. Acta 493 (2): 418–28.
- Aoyagi Y, Ikenaka T, Ichida F (1977). Comparative chemical structures of human alpha-fetoproteins from fetal serum and from ascites fluid of a patient with hepatoma. Cancer Res. 37 (10): 3663–7.
- Aoyagi Y, Ikenaka T, Ichida F (1978). Copper(II)-binding ability of human alpha-fetoprotein. Cancer Res. 38 (10): 3483–6.
- Aoyagi Y, Ikenaka T, Ichida F (1979). alpha-Fetoprotein as a carrier protein in plasma and its bilirubin-binding ability. Cancer Res. 39 (9): 3571–4.
- Torres JM, Anel A, Uriel J (1992). Alpha-fetoprotein-mediated uptake of fatty acids by human T lymphocytes. J. Cell. Physiol. 150 (3): 456–62.
- Greenberg F, Faucett A, Rose E, et al. (1992). Congenital deficiency of alpha-fetoprotein. Am. J. Obstet. Gynecol. 167 (2): 509–11.
- Bansal V, Kumari K, Dixit A, Sahib MK (1991). Interaction of human alpha fetoprotein with bilirubin. Indian J. Exp. Biol. 28 (7): 697–8.
- Pucci P, Siciliano R, Malorni A, et al. (1991). Human alpha-fetoprotein primary structure: a mass spectrometric study. Biochemistry 30 (20): 5061–6.
- Liu MC, Yu S, Sy J, et al. (1985). Tyrosine sulfation of proteins from the human hepatoma cell line HepG2. Proc. Natl. Acad. Sci. U.S.A. 82 (21): 7160–4.
- Gibbs PE, Zielinski R, Boyd C, Dugaiczyk A (1987). Structure, polymorphism, and novel repeated DNA elements revealed by a complete sequence of the human alpha-fetoprotein gene. Biochemistry 26 (5): 1332–43.
- Sakai M, Morinaga T, Urano Y, et al. (1985). The human alpha-fetoprotein gene. Sequence organization and the 5' flanking region. J. Biol. Chem. 260 (8): 5055–60.
- Ruoslahti E, Pihko H, Vaheri A, et al. (1975). Alpha fetoprotein: structure and expression in man and inbred mouse strains under normal conditions and liver injury. Johns Hopkins Med. J. Suppl. 3: 249–55.
- Urano Y, Sakai M, Watanabe K, Tamaoki T (1985). Tandem arrangement of the albumin and alpha-fetoprotein genes in the human genome. Gene 32 (3): 255–61.
- Beattie WG, Dugaiczyk A (1983). Structure and evolution of human alpha-fetoprotein deduced from partial sequence of cloned cDNA. Gene 20 (3): 415–22.
- Morinaga T, Sakai M, Wegmann TG, Tamaoki T (1983). Primary structures of human alpha-fetoprotein and its mRNA. Proc. Natl. Acad. Sci. U.S.A. 80 (15): 4604–8.
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