Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINA5
Cytogenetic location: 14q32.13 Genomic coordinates (GRCh38): 14:94,581,426-94,593,118 (from NCBI)
Marlar and Griffin (1980) identified in normal plasma a protein inhibitor of activated protein C (612283). Protein C is a vitamin K-dependent serine protease zymogen present in human plasma. Activated protein C is a potent anticoagulant.
Suzuki et al. (1987) determined the sequence of cDNA for human protein C inhibitor (PCI). A high degree of homology of the deduced amino acid sequence to that of other known inhibitors clearly demonstrated that protein C inhibitor is a member of the superfamily of serine protease inhibitors including alpha-1-antichymotrypsin (AACT; 107280), alpha-1-antitrypsin (AAT; PI; 107400), antithrombin III (AT3; 107300), and angiotensinogen (AGT; 106150).
Protein C inhibitor is sometimes referred to as plasminogen activator inhibitor-3 (PAI3) because it also inhibits plasminogen activators (Meijers and Chung, 1991). Plasminogen activator inhibitor-1 (PAI1; 173360) has structural similarities to PCI.
Meijers and Chung (1991) determined that the SERPINA5 gene contains 5 exons spanning 11.5 kb.
By PCR analysis of human-hamster hybrid cell lines, Meijers and Chung (1991) assigned the PROCI gene to chromosome 14.
Using pulsed-field gel electrophoresis, Billingsley et al. (1993) showed that the PCI gene is located in a cluster in 14q32.1 with other members of the serine protease inhibitor (serpin) superfamily: AACT, which is very close to PCI; PI, which is approximately 220 kb from PCI; and corticosteroid binding globulin (CBG; 122500). The PI-like gene (PIL; 107410), which is not expressed, lies between PI and CBG.
Meijers and Chung (1991) noted that the organization of the PCI gene is similar to that of PI and AACT, both of which map to chromosome 14, suggesting a recent evolution of these genes from a common ancestor.
Yasuda et al. (1992) studied an electrophoretic polymorphism of human plasma PCI. The combined techniques of polyacrylamide gel isoelectric focusing and immunoblotting with 3 different antibodies resolved the plasma PCI into several isoprotein bands. Two common phenotypes were recognized and family studies showed that they represented homozygosity or heterozygosity for 2 autosomal codominant alleles, PCI*1 and PCI*2. A population study of plasma samples collected from 977 Japanese persons indicated that the frequencies of these alleles were 0.988 and 0.012, respectively. Ashbourne et al. (1993) demonstrated a 2-allele RFLP of the PCI gene.
Deficiency of protein C inhibitor was thought at one time to be the basic cause of combined deficiency of coagulation factors V and VIII (227300). This was disproved in part by the demonstration that the PCI gene maps to chromosome 14 (Billingsley et al., 1993) and the clinical phenotype of the combined coagulation factor deficiency maps to chromosome 18 (Nichols et al., 1997). Sadler (1997) pointed out that before the study by Nichols et al. (1997), deficiency of PCI as the basic defect had been excluded on several grounds.
Ashbourne, K. J., Byth, B. C., Meijers, J. C. M., Cox, D. W. Polymorphism of the protein C inhibitor (PCI) gene on chromosome 14. Hum. Molec. Genet. 2: 92 only, 1993. [PubMed: 8098248] [Full Text: https://doi.org/10.1093/hmg/2.1.92]
Billingsley, G. D., Walter, M. A., Hammond, G. L., Cox, D. W. Physical mapping of four serpin genes: alpha-1-antitrypsin, alpha-1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome 14q32.1. Am. J. Hum. Genet. 52: 343-353, 1993. [PubMed: 8381582]
Marlar, R. A., Griffin, J. H. Deficiency of protein C inhibitor in combined factor V/VIII deficiency disease. J. Clin. Invest. 66: 1186-1189, 1980. [PubMed: 6253526] [Full Text: https://doi.org/10.1172/JCI109952]
Meijers, J. C., Chung, D. W. Organization of the gene coding for human protein C inhibitor (plasminogen activator inhibitor-3): assignment of the gene to chromosome 14. J. Biol. Chem. 266: 15028-15034, 1991. [PubMed: 1714450]
Nichols, W. C., Seligsohn, U., Zivelin, A., Terry, V. H., Arnold, N. D., Siemieniak, D. R., Kaufman, R. J., Ginsburg, D. Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping. J. Clin. Invest. 99: 596-601, 1997. [PubMed: 9045860] [Full Text: https://doi.org/10.1172/JCI119201]
Sadler, J. E. Combined factors V and VIII deficiency climbs onto the map. (Editorial) J. Clin. Invest. 99: 555-556, 1997. [PubMed: 9045852] [Full Text: https://doi.org/10.1172/JCI119193]
Suzuki, K., Deyashiki, Y., Nishioka, J., Kurachi, K., Akira, M., Yamamoto, S., Hashimoto, S. Characterization of a cDNA for human protein C inhibitor: a new member of the plasma serine protease inhibitor superfamily. J. Biol. Chem. 262: 611-616, 1987. [PubMed: 3027058]
Yasuda, T., Nadano, D., Iida, R., Tanaka, Y., Nakanaga, M., Kishi, K. Discovery of a genetic polymorphism of human plasma protein C inhibitor (PCI): genetic survey utilizing isoelectric focusing followed by immunoblotting, immunological and biochemical characterization. Hum. Genet. 89: 265-269, 1992. [PubMed: 1318261] [Full Text: https://doi.org/10.1007/BF00220537]