HGNC Approved Gene Symbol: AFP
SNOMEDCT: 716697002;
Cytogenetic location: 4q13.3 Genomic coordinates (GRCh38): 4:73,436,221-73,456,174 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q13.3 | [Hereditary persistence of alpha-fetoprotein] | 615970 | Autosomal dominant | 3 |
| Alpha-fetoprotein deficiency | 615969 | Autosomal recessive | 3 |
Alpha-fetoprotein (AFP) is a major plasma protein in fetal serum, where it is produced by the yolk sac and liver. Transcription of the gene rapidly declines after birth, and very low levels are already reached in the first 2 years of life (review by Schieving et al., 2014).
The AFP gene is a member of a multigenic family that comprises the related genes encoding albumin (ALB; 103600), alpha-albumin, or afamin (AFM; 104145), and vitamin D-binding protein, otherwise known as group-specific component (GC; 139200) (Gabant et al., 2002). These 4 genes are highly homologous and lie in tandem on the long arm of chromosome 4 (review by Schieving et al., 2014).
By means of restriction endonuclease mapping, Ingram et al. (1981) showed that the AFP and albumin genes in the mouse are in tandem, 13.5 kb pairs apart, with the albumin gene on the 5-prime side of the AFP gene. Thus, they are transcribed from the same strand of DNA. The order is, however, different from that expected by analogy with the gamma and beta globin genes; with the presumed switch from AFP to albumin, one might expect their position to be reversed from that observed.
Beattie and Dugaiczyk (1982) found extensive DNA sequence homology between human AFP and the third domain of serum albumin. AFP appears to have evolved more rapidly than albumin.
Morinaga et al. (1983) reported that the human mature human alpha-fetoprotein contains 590 amino acids, resulting from cleavage of a 19-amino acid signal sequence. Human alpha-fetoprotein shares 66% identity with mouse alpha-fetoprotein and 39% identity with human albumin.
In mice, Tilghman and Belayew (1982) found a parallel accumulation of AFP and albumin mRNAs before birth, followed by a selective decrease in AFP mRNA after birth. The decrease in AFP mRNA was the result of decrease in transcription of the AFP gene, as measured by an in vitro nuclear transcription assay. They suggested a model for hepatic expression of the AFP and albumin gene cluster in which transcription of the 2 genes is activated simultaneously during differentiation and each gene is thereafter modulated independently in committed cells.
Voigtlander and Vogel (1985) commented on the fact that not only is AFP low in maternal serum and amniotic fluid in pregnancies with a Down syndrome (190685) fetus but also serum albumin is low (according to most reports) in Down syndrome patients of all ages. (Total serum protein may be normal because of an increase in gamma globulins.) A defect in a regulatory mechanism common to the 2 proteins was suggested.
In the mouse liver, the adult basal levels of AFP mRNA is determined by a gene called regulator of alpha-fetoprotein (raf) (Olsson et al., 1977), and the inducibility of AFP mRNA during regeneration is regulated by a gene termed rif (regulator of induction of alpha-fetoprotein) (Belayew and Tilghman, 1982). The human homolog of mouse raf is ZHX2 (609185). The raf and rif genes are not linked to the AFP gene or to each other (Vogt et al., 1987); it is possible that these regulatory genes function through trans-acting regulatory factors that interact with cis-acting elements of the AFP gene. Watanabe et al. (1987) described experiments showing that the 5-prime flanking region of the human AFP gene contains transcription control elements with characteristics of enhancers.
Using transgenic mouse strains in which integrated AFP gene constructs exhibited raf regulation, Vogt et al. (1987) showed that a DNA-binding sequence for the raf product is present in the proximal 7.6 kb of DNA 5-prime to the AFP gene. The evolutionarily related and closely linked albumin gene is not affected by raf, nor is another oncofetal protein, gamma-glutamyl transpeptidase (GGT1; 612346). However, raf does regulate the level of at least one other structural gene termed H19 (103280).
Perincheri et al. (2005) determined that persistent expression of Afp and H19 in BALB/cJ mice is due to the insertion of a murine endogenous retrovirus within the first intron of the Zhx2 gene, which leads predominantly to expression of an aberrant transcript that no longer encodes a functional transcriptional repressor. Liver-specific overexpression of a Zhx2 transgene restored wildtype H19 repression on a BALB/cJ background.
Xie et al. (2008) identified Zbtb20 (606025) as a major regulator of Afp transcription in adult mouse liver. Targeted disruption of the Zbtb20 gene in mouse liver resulted in adult Afp mRNA levels about 3,000-fold higher than those in normal adult liver. Afp mRNA was activated gradually in both wildtype and Zbtb20-knockout fetal liver, but only wildtype liver showed a precipitous decline in Afp expression in the first 4 weeks of life. In Zbtb20-knockout liver, Afp mRNA levels declined less than 5-fold and remained high, suggesting a failure of transcriptional shutoff. Chromatin immunoprecipitation analysis and reporter gene assays confirmed that Zbtb20 bound and inhibited transcription of Afp in a dose-dependent manner. Furthermore, RT-PCR and Western blot analysis demonstrated an inverse relationship in Zbtb20 and Afp expression in normal fetal and adult liver. Xie et al. (2008) concluded that ZBTB20 is a key regulator that blocks AFP expression in adult liver.
AFP as a Biomarker of Disease
Staples (1986) demonstrated high serum AFP in 6 members of 2 generations of the family of a man with testicular carcinoma. Hereditary spherocytosis (see 182900) was segregating independently in this family. Staples (1986) also indicated that alcoholic steatosis of the liver can cause reversible elevation of AFP.
In nephrotic syndrome type 1 (NPHS1; 256300), an autosomal recessive disorder frequent in Finland, alpha-fetoprotein is increased in the maternal blood and amniotic fluid, which is an expression of renal loss of protein (Morris et al., 1995).
Schieving et al. (2014) reviewed the relevance of AFP as a biomarker of disease in clinical practice, including obstetrics, liver disease and oncology, and congenital hypothyroidism. Uses in obstetrics include screening for neural tube defects, such as spina bifida and anencephaly, and for Down syndrome (190685). Neurologic disorders associated with increased serum AFP include ataxia-telangiectasia (AT; 208900), AOA2 (SCAN2; 606002), AOA3 (615217), and possibly some mitochondrial disorders.
The AFP gene contains 15 exons (Sakai et al., 1985).
Hammer et al. (1987) described enhancer elements in the 5-prime flanking region of the mouse AFP gene.
Gibbs et al. (1987) identified 4 types of repetitive sequence elements in the introns and flanking regions of the human AFP gene. One of these was apparently a novel structure designated Xba. The others were Alu, X, and Kpn elements. X, Xba, and Kbn elements are not present in the human albumin gene and Alu sequences are present in different positions. From phylogenetic evidence, it appears that Alu elements were inserted into the AFP gene at some time postdating the mammalian radiation, 85 million years ago.
Using in situ hybridization, Harper and Dugaiczyk (1983) mapped the AFP gene to chromosome 4q11-q22, in the same region as the albumin gene.
Magenis et al. (1989) used in situ hybridization to localize the ALB and the AFP genes to orangutan chromosome 3q11-q15 and gorilla chromosome 3q11-q22.
Minghetti et al. (1985) found a high rate of silent substitutions for both alpha-fetoprotein and albumin genes. The rates of effective substitution and amino acid changes were also very high but, in contrast to silent substitutions, they were found to be higher for alpha-fetoprotein than for albumin by about 70%. For alpha-fetoprotein, the rate of effective substitution may approach that for nonfunctional pseudogenes. This high rate suggests that alpha-fetoprotein can tolerate a great deal of molecular variation without its function being impaired.
Hereditary Persistence of Alpha-Fetoprotein
In members of a large Scottish kindred with hereditary persistence of alpha-fetoprotein (HPAFP; 615970), McVey et al. (1993) identified a heterozygous mutation in the AFP gene (104150.0001).
In affected individuals from 2 unrelated families with HPAFP, Alj et al. (2004) identified 2 different heterozygous mutations in the distal (104150.0001) and proximal (104150.0004) HNF1 (142410) binding regions in the promoter of the AFP gene. Both mutations resulted in increased affinity of the promoters for HNF1, resulting in increased levels of gene transcription. The findings highlighted the importance of HNF1 in AFP gene expression. Alj et al. (2004) suggested that unexplained increased AFP should led to AFP promoter gene sequencing to avoid inappropriate explorations or treatment decisions, as HFAPF is a benign trait.
Alpha-Fetoprotein Deficiency
In 2 Arab families with congenital deficiency of AFP (AFPD; 615969), Sharony et al. (2004) identified a homozygous 2-bp deletion in the AFP gene (104150.0002). The affected individuals were asymptomatic and developed normally.
Petit et al. (2009) identified a homozygous truncating mutation in the AFP gene (104150.0003) in an Algerian infant who showed normal growth and development. The deficiency was noted by the absence of AFP in the maternal serum and amniotic fluid during the second trimester of pregnancy.
The similarity in physical properties of AFP and albumin (ALB; 103600) and the fact that their presence is inversely related suggested that AFP is the fetal counterpart of serum albumin. The alpha-fetoprotein and albumin genes are syntenic; this may represent an ontogenically significant arrangement with switch from AFP to albumin, comparable to the hemoglobin F to hemoglobin A switch (see 141800). Mammalian AFP and serum albumin genes are thought to have arisen through duplication of an ancestral gene 300 to 500 million years ago (summary by Ingram et al., 1981).
Gabant et al. (2002) used gene targeting to show that AFP is not required for embryonic development. AFP-null embryos developed normally, and individually transplanted homozygous embryos could develop in an AFP-deficient microenvironment. Whereas mutant homozygous adult males were viable and fertile, AFP-null females were infertile. Analysis of these mice indicated that the defect was caused by a dysfunction of the hypothalamic/pituitary system, leading to anovulation.
As part of an extensive screening program for spina bifida, a large Scottish kindred spanning 5 generations was identified as having hereditary persistence of alpha-fetoprotein (HPAFP; 615970). Affected persons had mean serum AFP levels 23-fold higher than normal controls. These raised levels were, however, far below the levels seen in the fetus. McVey et al. (1993) showed by sequence analysis of the 5-prime flanking sequences of the AFP gene that in this family a G-to-A transition at position -119 was associated with the trait. This substitution occurs in a potential HNF1 binding site and increases the similarity of the sequence to a consensus HNF1 recognition site. In a competitive gel retardation assay, the mutant sequence bound HNF1-alpha (142410) more tightly than the wildtype sequence. Furthermore, 5-prime-flanking sequences of the human AFP gene containing the G-to-A substitution directed a higher level of chloramphenicol acetyltransferase (CAT) expression in transfected human hepatoma cells than the wildtype sequences. The findings not only provided an explanation for the findings in this family, but also highlighted the importance of this HNF1 binding site in the developmental regulation of the AFP gene. The substitution is similar to those that cause hereditary persistence of fetal hemoglobin (e.g., 142200.0026; a G-A substitution at -117 of the HBG1 gene).
Alj et al. (2004) identified a heterozygous -119G-A mutation in the AFP gene in 4 members of an Indian family with HPAFP. The mutation occurs in the distal HNF1 binding site of the promoter.
Petit et al. (2009) referred to this deletion as c.882delCT based on numbering from the ATG start codon.
In 2 Arab families with congenital deficiency of AFP (AFPD; 615969), Sharony et al. (2004) identified a 2-bp deletion in exon 8 of the AFP gene, c.930_931delCT, resulting in a frameshift and stop codon (Thr294fs25Ter) that truncated the protein to 318 amino acids. All affected children were homozygous for the deletion, as was 1 of the fathers; affected individuals were asymptomatic and developed normally. Sharony et al. (2004) stated that this was the first demonstration that deficiency of AFP is compatible with normal human fetal development and normal reproduction in males.
In an Algerian male infant with congenital deficiency of AFP (AFPD; 615969), Petit et al. (2009) identified a homozygous c.543G-A transition in exon 5 of the AFP gene, resulting in a trp181-to-ter (W181X) substitution. There was no detectable AFP in the mother's serum or amniotic fluid during the second trimester of pregnancy, but fetal ultrasounds were normal, and the infant was healthy at birth. In the amniotic fluid, albumin was decreased, whereas alpha-1 and beta protein fractions were increased, suggesting that AFP deficiency may modify the distribution of protein fractions as a compensatory mechanism.
In affected members of an Italian family with hereditary persistence of alpha-fetoprotein (HPAFP; 615970), Alj et al. (2004) identified a heterozygous -55C-A transversion in a conserved region in the proximal putative HNF1 (142410) binding region of the AFP promoter. The mutation was not found in 50 control individuals. In vitro functional expression studies showed that the mutation resulted in increased affinity of the promoter for HNF1, resulting in increased levels of gene transcription.
Alj, Y., Georgiakaki, M., Savouret, J.-F., Mal, F., Attali, P., Pelletier, G., Fourre, C., Milgrom, E., Buffet, C., Guiochon-Mante, A., Perlemuter, G. Hereditary persistence of alpha-fetoprotein is due to both proximal and distal hepatocyte nuclear factor-1 site mutations. Gastroenterology 126: 308-317, 2004. [PubMed: 14699509] [Full Text: https://doi.org/10.1053/j.gastro.2003.10.073]
Beattie, W. G., Dugaiczyk, A. Structure and evolution of human alpha-fetoprotein deduced from partial sequence of cloned cDNA. Gene 20: 415-422, 1982. [PubMed: 6187626] [Full Text: https://doi.org/10.1016/0378-1119(82)90210-4]
Belayew, A., Tilghman, S. M. Genetic analysis of alpha-fetoprotein synthesis in mice. Molec. Cell. Biol. 2: 1427-1435, 1982. [PubMed: 6186903] [Full Text: https://doi.org/10.1128/mcb.2.11.1427-1435.1982]
D'Eustachio, P., Ingram, R. S., Tilghman, S. M., Ruddle, F. H. Murine alpha-fetoprotein and albumin: two evolutionarily linked proteins encoded on the same mouse chromosome. Somat. Cell Genet. 7: 289-294, 1981. [PubMed: 6170120] [Full Text: https://doi.org/10.1007/BF01538854]
Eiferman, F. A., Young, P. R., Scott, R. W., Tilghman, S. M. Intragenic amplification and divergence in the mouse alpha-fetoprotein gene. Nature 294: 713-718, 1981. [PubMed: 6172714] [Full Text: https://doi.org/10.1038/294713a0]
Gabant, P., Forrester, L., Nichols, J., Van Reeth, T., De Mees, C., Pajack, B., Watt, A., Smitz, J., Alexandre, H., Szpirer, C., Szpirer, J. Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility. Proc. Nat. Acad. Sci. 99: 12865-12870, 2002. [PubMed: 12297623] [Full Text: https://doi.org/10.1073/pnas.202215399]
Gibbs, P. E. M., Zielinski, R., Boyd, C., Dugaiczyk, A. Structure, polymorphism, and novel repeated DNA elements revealed by a complete sequence of the human alpha-fetoprotein gene. Biochemistry 26: 1332-1343, 1987. [PubMed: 2436661] [Full Text: https://doi.org/10.1021/bi00379a020]
Gorin, M. B., Tilghman, S. M. Structure of the alpha-fetoprotein gene in the mouse. Proc. Nat. Acad. Sci. 77: 1351-1355, 1980. [PubMed: 6154931] [Full Text: https://doi.org/10.1073/pnas.77.3.1351]
Hammer, R. E., Krumlauf, R., Camper, S. A., Brinster, R. L., Tilghman, S. M. Diversity of alpha-fetoprotein gene expression in mice is generated by a combination of separate enhancer elements. Science 235: 53-58, 1987. [PubMed: 2432657] [Full Text: https://doi.org/10.1126/science.2432657]
Harper, M. E., Dugaiczyk, A. Linkage of the evolutionarily-related serum albumin and alpha-fetoprotein genes within q11-22 of human chromosome 4. Am. J. Hum. Genet. 35: 565-572, 1983. [PubMed: 6192711]
Ingram, R. S., Scott, R. W., Tilghman, S. M. Alpha-fetoprotein and albumin genes are in tandem in the mouse genome. Proc. Nat. Acad. Sci. 78: 4694-4698, 1981. [PubMed: 6170978] [Full Text: https://doi.org/10.1073/pnas.78.8.4694]
Jagodzinski, L. L., Sargent, T. D., Yang, M., Glackin, C., Bonner, J. Sequence homology between RNAs encoding rat alpha-fetoprotein and rat serum albumin. Proc. Nat. Acad. Sci. 78: 3521-3525, 1981. [PubMed: 6167988] [Full Text: https://doi.org/10.1073/pnas.78.6.3521]
Magenis, R. E., Luo, X. Y., Dugaiczyk, A., Ryan, S. C., Oosterhuis, J. E. Chromosomal localization of the albumin and alpha-fetoprotein genes in the orangutan (Pongo pygmaeus) and gorilla (Gorilla gorilla). (Abstract) Cytogenet. Cell Genet. 51: 1037, 1989.
McVey, J. H., Michaelides, K., Hansen, L. P., Ferguson-Smith, M., Tilghman, S., Krumlauf, R., Tuddenham, E. G. D. A G-to-A substitution in an HNF I binding site in the human alpha-fetoprotein gene is associated with hereditary persistence of alpha-fetoprotein (HPAFP). Hum. Molec. Genet. 2: 379-384, 1993. [PubMed: 7684942] [Full Text: https://doi.org/10.1093/hmg/2.4.379]
Minghetti, P. P., Law, S. W., Dugaiczyk, A. The rate of molecular evolution of alpha-fetoprotein approaches that of pseudogenes. Molec. Biol. Evol. 2: 347-358, 1985. [PubMed: 2452956] [Full Text: https://doi.org/10.1093/oxfordjournals.molbev.a040350]
Morinaga, T., Sakai, M., Wegmann, T. G., Tamaoki, T. Primary structures of human alpha-fetoprotein and its mRNA. Proc. Nat. Acad. Sci. 80: 4604-4608, 1983. [PubMed: 6192439] [Full Text: https://doi.org/10.1073/pnas.80.15.4604]
Morris, J., Ellwood, D., Kennedy, D., Knight, J. Amniotic alpha-fetoprotein in the prenatal diagnosis of congenital nephrotic syndrome of the Finnish type. Prenatal Diag. 15: 482-485, 1995. [PubMed: 7543998] [Full Text: https://doi.org/10.1002/pd.1970150513]
Olsson, M., Lindahl, G., Ruoslahti, E. Genetic control of alpha-fetoprotein synthesis in the mouse. J. Exp. Med. 145: 819-827, 1977. [PubMed: 67170] [Full Text: https://doi.org/10.1084/jem.145.4.819]
Perincheri, S., Dingle, R. W. C., Peterson, M. L., Spear, B. T. Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene. Proc. Nat. Acad. Sci. 102: 396-401, 2005. [PubMed: 15626755] [Full Text: https://doi.org/10.1073/pnas.0408555102]
Petit, F. M., Hebert, M., Picone, O., Brisset, S., Maurin, M.-L., Parisot, F., Capel, L., Benattar, C., Senat, M.-V., Tachdjian, G., Labrune, P. A new mutation in the AFP gene responsible for a total absence of alpha feto-protein on second trimester maternal serum screening for Down syndrome. Europ. J. Hum. Genet. 17: 387-390, 2009. [PubMed: 18854864] [Full Text: https://doi.org/10.1038/ejhg.2008.186]
Ruoslahti, E., Terry, W. D. Alpha fetoprotein and serum albumin show sequence homology. Nature 260: 804-805, 1976. [PubMed: 57576] [Full Text: https://doi.org/10.1038/260804a0]
Sakai, M., Morinaga, T., Urano, Y., Watanabe, K., Wegmann, T. G., Tamaoki, T. The human alpha-fetoprotein gene: sequence organization and the 5-prime flanking region. J. Biol. Chem. 260: 5055-5060, 1985. [PubMed: 2580830]
Schieving, J. H., de Vries, M., van Vugt, J. M. G., Weemaes, C., van Deuren, M., Nicolai, J., Wevers, R. A., Willemsen, M. A. Alpha-fetoprotein, a fascinating protein and biomarker in neurology. Europ. J. Paediat. Neurol. 18: 243-248, 2014. [PubMed: 24120489] [Full Text: https://doi.org/10.1016/j.ejpn.2013.09.003]
Sharony, R., Zadik, I., Parvari, R. Congenital deficiency of alpha feto-protein. Europ. J. Hum. Genet. 12: 871-874, 2004. [PubMed: 15280901] [Full Text: https://doi.org/10.1038/sj.ejhg.5201246]
Staples, J. Alphafetoprotein, cancer, and benign conditions. (Letter) Lancet 328: 1277 only, 1986. Note: Originally Volume II. [PubMed: 2431238] [Full Text: https://doi.org/10.1016/s0140-6736(86)92700-5]
Szpirer, J., Levan, G., Thorn, M., Szpirer, C. Gene mapping in the rat by mouse-rat somatic cell hybridization: synteny of the albumin and alpha-fetoprotein genes and assignment to chromosome 14. Cytogenet. Cell Genet. 38: 142-149, 1984. [PubMed: 6205824] [Full Text: https://doi.org/10.1159/000132047]
Tilghman, S. M., Belayew, A. Transcriptional control of the murine albumin/alpha-fetoprotein locus during development. Proc. Nat. Acad. Sci. 79: 5254-5257, 1982. [PubMed: 6182563] [Full Text: https://doi.org/10.1073/pnas.79.17.5254]
Urano, Y., Sakai, M., Watanabe, K., Tamaoki, T. Tandem arrangement of the albumin and alpha-fetoprotein genes in the human genome. Gene 32: 255-261, 1984. [PubMed: 6085063] [Full Text: https://doi.org/10.1016/0378-1119(84)90001-5]
Vogt, T. F., Solter, D., Tilghman, S. M. Raf, a trans-acting locus, regulates the alpha-fetoprotein gene in a cell-autonomous manner. Science 236: 301-303, 1987. [PubMed: 2436297] [Full Text: https://doi.org/10.1126/science.2436297]
Voigtlander, T., Vogel, F. Low alpha-fetoprotein and serum albumin levels in Morbus Down may point to a common regulatory mechanism. Hum. Genet. 71: 276-277, 1985. [PubMed: 2415443] [Full Text: https://doi.org/10.1007/BF00284593]
Watanabe, K., Saito, A., Tamaoki, T. Cell-specific enhancer activity in a far upstream region of the human alpha-fetoprotein gene. J. Biol. Chem. 262: 4812-4818, 1987. [PubMed: 2435718]
Xie, Z., Zhang, H., Tsai, W., Zhang, Y., Du, Y., Zhong, J., Szpirer, C., Zhu, M., Cao, X., Barton, M. C., Grusby, M. J., Zhang, W. J. Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver. Proc. Nat. Acad. Sci. 105: 10859-10864, 2008. [PubMed: 18669658] [Full Text: https://doi.org/10.1073/pnas.0800647105]