Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINA10
Cytogenetic location: 14q32.13 Genomic coordinates (GRCh38): 14:94,280,460-94,293,268 (from NCBI)
SERPINA10 encodes protein Z-dependent protease inhibitor precursor (ZPI) that inhibits the activated coagulation factors X (613872) and XI (264900) (Van de Water et al., 2004).
New et al. (1996) isolated a gene encoding a plasma protein by constructing and screening a cDNA library with RNA isolated from rat liver at 48 hours after 70 to 90% hepatectomy. New et al. (1996) stated that the expression of acute phase inflammatory proteins should be substantially diminished, thereby reducing the 'background' and facilitating the identification of genes associated with regeneration. They identified several clones that were upregulated in the regenerating liver. They isolated 1 clone, termed 'regeneration-associated serpin-1' (Rasp1), that was expressed in normal liver but was upregulated approximately 3- to 4-fold by 48 hours after hepatectomy. DNA sequence analysis showed that the Rasp1 gene encodes a novel 436-amino acid secreted protein. Moderate homology was found with several members of the serpin family of serine-protease inhibitors. The 1.7-kb Rasp1 mRNA was highly expressed in rat liver, but not in brain, heart, kidney, lung, testis, or spleen. It was found in normal and hepatectomy rat plasma.
Using micropeptide sequence analysis and database searching, followed by PCR of a human fetal liver cDNA library with primers based on rat Rasp1 and by probing of a liver cDNA library, Han et al. (1999) isolated a cDNA encoding ZPI. Sequence analysis predicted that the 444-amino acid protein, which is 78% identical to rat Rasp1 and 25 to 35% homologous with other serpin family members, has a 21-residue signal peptide and 5 potential N-linked glycosylation sites. The putative P1 residue at the reactive centers of ZPI and Rasp1 is a tyrosine at position 387. Northern blot analysis revealed abundant expression of a 2.4-kb transcript in liver but not in heart, brain, placenta, lung, liver, skeletal muscle, kidney, or pancreas. Western blot analysis showed that recombinant ZPI is expressed as a 72-kD protein with high PROZ-dependent factor Xa inhibition activity, whereas mutants of tyr387 show little or no activity.
Scott (2000) mapped the SERPINA10 gene to chromosome 14 based on sequence similarity between the SERPINA10 sequence (GenBank AF181467) and a chromosome 14 clone (GenBank AL117259).
By biochemical purification, Han et al. (1998) isolated the 72-kD plasma protein ZPI. They showed that incubation of protein Z (PROZ; 176895), a vitamin K-dependent plasma protein, forms a calcium ion-dependent complex with activated factor X (factor Xa) at phospholipid surfaces. The PROZ-factor Xa interaction reduces the rate of coagulation factor Xa inhibition by antithrombin (see 107300) but enhances the inhibition of factor Xa mediated by ZPI.
By functional analysis, Han et al. (1999) determined that ZPI inhibits factor Xa but not chymotrypsin, cathepsin G, thrombin, meizothrombin, plasmin, trypsin, leukocyte elastase, tissue plasminogen activator, urinary plasminogen activator, APC, factor VIIa, or factor IXa. By further analysis of coagulation in vitro and in vivo, Yin et al. (2000) confirmed that PROZ is a cofactor of ZPI in factor Xa inhibition.
Associations Pending Confirmation
Using denaturing high-performance liquid chromatography, Van de Water et al. (2004) screened the coding region of the ZPI gene for mutations; they identified 16 mutations/polymorphisms within the coding region of ZPI, including 2 nonsense mutations that generated stop codons at residues arg67 and trp303 (605721.0001). They identified nonsense mutations within the ZPI gene in 11 (4.4%) of 250 patients with thrombosis (see 188050) compared with 2 (0.8%) of 250 controls. The difference in distribution of stop codon mutations between thrombosis patients and controls was significant (p = 0.02), with an odds ratio of 5.7 (95% CI, 1.25-26.0). The results suggested an association between ZPI deficiency and venous thrombosis, and Van de Water et al. (2004) suggested that ZPI deficiency is a form of thrombophilia.
This variant, formerly titled VENOUS THROMBOSIS, SUSCEPTIBILITY TO, has been reclassified because its contribution to the development of venous thrombosis has not been confirmed.
In 8 of 250 patients with venous thrombosis (see 188050), Van de Water et al. (2004) identified a heterozygous trp303-to-ter (W303X) mutation in the ZPI gene. The mutation was not found in any of 250 control individuals. Deep venous thrombosis had occurred in most of the patients, and pulmonary embolism had occurred in at least 2.
Han, X., Fiehler, R., Broze, G. J., Jr. Isolation of protein Z-dependent plasma protease inhibitor. Proc. Nat. Acad. Sci. 95: 9250-9255, 1998. [PubMed: 9689066] [Full Text: https://doi.org/10.1073/pnas.95.16.9250]
Han, X., Huang, Z. F., Fiehler, R., Broze, G. J., Jr. The protein Z-dependent protease inhibitor is a serpin. Biochemistry 38: 11073-11078, 1999. [PubMed: 10460162] [Full Text: https://doi.org/10.1021/bi990641a]
New, L., Liu, K., Kamali, V., Plowman, G., Naughton, B. A., Purchio, A. F. cDNA cloning of rasp-1, a novel gene encoding a plasma protein associated with liver regeneration. Biochem. Biophys. Res. Commun. 223: 404-412, 1996. [PubMed: 8670294] [Full Text: https://doi.org/10.1006/bbrc.1996.0906]
Scott, A. F. Personal Communication. Baltimore, Md. 9/14/2000.
Van de Water, N., Tan, T., Ashton, F., O'Grady, A., Day, T., Browett, P., Ockelford, P., Harper, P. Mutations within the protein Z-dependent protease inhibitor gene are associated with venous thromboembolic disease: a new form of thrombophilia. Brit. J. Haemat. 127: 190-194, 2004. [PubMed: 15461625] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.05189.x]
Yin, Z. F., Huang, Z. F., Cui, J., Fiehler, R., Lasky, N., Ginsburg, D., Broze, G. J., Jr. Prothrombotic phenotype of protein Z deficiency. Proc. Nat. Acad. Sci. 97: 6734-6738, 2000. [PubMed: 10829076] [Full Text: https://doi.org/10.1073/pnas.120081897]