Alternative titles; symbols
HGNC Approved Gene Symbol: ANXA5
Cytogenetic location: 4q27 Genomic coordinates (GRCh38): 4:121,667,946-121,696,980 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q27 | {Pregnancy loss, recurrent, susceptibility to, 3} | 614391 | Autosomal dominant | 3 |
PP4 is an anticoagulant protein that acts as an indirect inhibitor of the thromboplastin-specific complex, which is involved in the blood coagulation cascade. It has a relative molecular weight of about 35,000 and is present in placental tissue to the extent of about 50 mg per placenta with very little secretion into the maternal bloodstream. The PP4 cDNA encoded a protein of 320 amino acid residues. In addition to the PP4 cDNA, Grundmann et al. (1988) identified cDNA encoding a protein with 74% identity to PP4, which they termed PP4-X. PP4 and PP4-X belong to the lipocortin family, as judged by their homology to lipocortin I (151690) and calpactin I (114085). The placental anticoagulant protein called PAP, isolated by Funakoshi et al. (1987), may be the same protein. PP4 is also known as endonexin II.
Endonexin II is a member of the family of Ca(2+)-dependent phospholipid binding proteins, known as annexins, which bind to the phospholipids that are preferentially located on the cytosolic face of the plasma membrane. Kaplan et al. (1988) cloned endonexin II cDNA and expressed it in Escherichia coli. A single mRNA, approximately 1.6 kb long, was found to be expressed in human cell lines and placenta. The length of the cDNA clone was 1.59 kb. The cDNA predicted a 320-amino acid protein with a sequence in agreement with the previously determined partial amino acid sequence of endonexin II isolated from placenta.
Using a cDNA clone of endonexin II, Modi et al. (1989) assigned the ANXA5 gene to 4q28-q31 by in situ hybridization and Southern analysis of human-rodent cell hybrid DNAs. Tait et al. (1991) found a somewhat different localization which overlapped with the assignment of Modi et al. (1989). By in situ hybridization with a cDNA probe and by polymerase chain reaction (PCR) analysis of a human/hamster hybrid cell panel, they assigned the ANXA5 gene to 4q26-q28. The regional localization was supported by Southern blot analysis of a human cell line with a deletion in 4q23-q27. A compromise assignment might be 4q26-q28. Rodriguez-Garcia et al. (1996) mapped the homologous gene to mouse chromosome 3.
Annexin V forms the voltage-dependent Ca(2+) channels in phospholipid bilayers and was the first ion channel to be structurally and functionally characterized. Demange et al. (1994) outlined data indicating that key amino acid residues act as selectivity filters and voltage sensors, thereby regulating the permeability of the channel pore to ions.
Tzima et al. (2000) showed that annexin V bound to F-actin and gamma-actin (ACTG1; 102560), but not beta-actin (ACTB; 102630), in activated human platelets.
In 70 German patients with recurrent pregnancy loss (RPRGL3; 614391) who were known to carry neither factor V Leiden (612309.0001) nor a prothrombin (176930) mutation, Bogdanova et al. (2007) analyzed the ANXA5 gene and identified 4 consecutive nucleotide substitutions in the promoter region that were transmitted as a joint haplotype designated 'M2' (131230.0001). Carriers of the M2 haplotype had a 2- to 4-fold higher risk of RPRGL than noncarriers.
Brachvogel et al. (2003) found that heterozygous and homozygous Anxa5-deficient mice were born at expected mendelian ratios, were viable and fertile, and showed no obvious phenotypic or behavioral abnormalities.
In 70 German patients with recurrent pregnancy loss (RPRGL3; 614391) who were negative for factor V Leiden (612309.0001) and a known RPRGL-related prothrombin mutation (176930.0009), Bogdanova et al. (2007) analyzed the ANXA5 gene and identified 4 consecutive nucleotide substitutions in the promoter region, -19G-A, 1A-C, 27T-C, and 76G-A, that were transmitted as a joint haplotype, which they designated 'M2.' All substitutions changed a transcription factor consensus site or affected a nucleotide adjacent to it. Reporter gene assays revealed that when all 4 nucleotide substitutions were present, ANXA5 promoter activity was reduced to less than half (37% to 42%) of wildtype activity. Carriers of the M2 haplotype had a greater than 2-fold higher risk of RPRGL than noncarriers (odds ratio, 2.42) when using unselected controls; when compared to women with successful pregnancies and no previous history of pregnancy loss, carriers had an almost 4-fold higher risk of RPRGL (odds ratio, 3.88).
Bogdanova, N., Horst, J., Chlystun, M., Croucher, P. J. P., Nebel, A., Bohring, A., Todorova, A., Schreiber, S., Gerke, V., Krawczak, M., Markoff, A. A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss. Hum. Molec. Genet. 16: 573-578, 2007. [PubMed: 17339269] [Full Text: https://doi.org/10.1093/hmg/ddm017]
Brachvogel, B., Dikschas, J., Moch, H., Welzel, H., von der Mark, K., Hofmann, C., Poschl, E. Annexin A5 is not essential for skeletal development. Molec. Cell. Biol. 23: 2907-2913, 2003. [PubMed: 12665588] [Full Text: https://doi.org/10.1128/MCB.23.8.2907-2913.2003]
Demange, P., Voges, D., Benz, J., Liemann, S., Gottig, P., Berendes, R., Burger, A., Huber, R. Annexin V: the key to understanding ion selectivity and voltage regulation? Trends Biochem. Sci. 19: 272-276, 1994. [PubMed: 7519374] [Full Text: https://doi.org/10.1016/0968-0004(94)90002-7]
Funakoshi, T., Heimark, R. L., Hendrickson, L. E., McMullen, B. A., Fujikawa, K. Human placental anticoagulant protein: isolation and characterization. Biochemistry 26: 5572-5578, 1987. [PubMed: 2960376] [Full Text: https://doi.org/10.1021/bi00391a053]
Grundmann, U., Abel, K.-J., Bohn, H., Lobermann, H., Lottspeich, F., Kupper, H. Characterization of cDNA encoding human placental anticoagulant protein (PP4): homology with the lipocortin family. Proc. Nat. Acad. Sci. 85: 3708-3712, 1988. [PubMed: 2967495] [Full Text: https://doi.org/10.1073/pnas.85.11.3708]
Kaplan, R., Jaye, M., Burgess, W. H., Schlaepfer, D. D., Haigler, H. T. Cloning and expression of cDNA for human endonexin II, a Ca(2+) and phospholipid binding protein. J. Biol. Chem. 263: 8037-8043, 1988. [PubMed: 2967291]
Modi, W. S., Seuanez, H., Jaye, M., Kaplan, R., Haigler, H., O'Brien, S. J. Chromosomal mapping of the endonexin II gene. (Abstract) Cytogenet. Cell Genet. 51: 1046, 1989.
Modi, W. S., Seuanez, H. N., Jaye, M., Haigler, H. J., Kaplan, R., O'Brien, S. J. The human endonexin II (ENX2) gene is located at 4q28-q32. Cytogenet. Cell Genet. 52: 167-169, 1989. [PubMed: 2534288] [Full Text: https://doi.org/10.1159/000132870]
Rodriguez-Garcia, M. I., Kozak, C. A., Morgan, R. O., Fernandez, M. P. Mouse annexin V chromosomal localization, cDNA sequence conservation, and molecular evolution. Genomics 31: 151-157, 1996. [PubMed: 8824796] [Full Text: https://doi.org/10.1006/geno.1996.0026]
Tait, J. F., Frankenberry, D. A., Shiang, R., Murray, J. C., Adler, D. A., Disteche, C. M. Chromosomal localization of the human gene for annexin V (placental anticoagulant protein I) to 4q26-q28. Cytogenet. Cell Genet. 57: 187-192, 1991. [PubMed: 1683830] [Full Text: https://doi.org/10.1159/000133143]
Tzima, E., Trotter, P. J., Orchard, M. A., Walker, J. H. Annexin V relocates to the platelet cytoskeleton upon activation and binds to a specific isoform of actin. Europ. J. Biochem. 267: 4720-4730, 2000. [PubMed: 10903505] [Full Text: https://doi.org/10.1046/j.1432-1327.2000.01525.x]