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Gene Review

SERPING1  -  serpin peptidase inhibitor, clade G (C1...

Homo sapiens

Synonyms: C1 Inh, C1 esterase inhibitor, C1-INH, C1-inhibiting factor, C1IN, ...
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Disease relevance of SERPING1

  • BACKGROUND: Hereditary angioedema (HAE) is caused by heterozygous defects in the C1 inhibitor (C1-INH) gene (SERPING1/C1NH) [1].
  • Hereditary angioneurotic edema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous and submucosal edema caused by the deficiency of activated C1 esterase inhibitor protein (C1-INH, type I (C1NH): reduced serum antigen level, type II: reduced activity and normal serum antigen level) [2].
  • There is now accumulating evidence, obtained from studies in animals and observations in patients, that administration of C1-Inh may have a beneficial effect as well in other clinical conditions such as sepsis, cytokine-induced vascular leak syndrome, acute myocardial infarction, or other diseases [3].
  • In addition, StcE-treated C1-INH provides significantly increased serum resistance to E. coli K-12 over native C1-INH [4].
  • This study evaluates in dogs the effect of the C1-esterase inhibitor (C1-INH), a main inhibitor of the blood coagulation contact system, on the cardiovascular and respiratory dysfunction associated with endotoxic shock [5].
  • Mutations in this gene may play a role in age related macular degeneration [6].

High impact information on SERPING1

  • This autoantibody was isolated from a patient with a novel variant of acquired angioedema and C1-Inh dysfunction [7].
  • C1-esterase inhibitor (C1-Inh) therapy was introduced in clinical medicine about 25 years ago as a replacement therapy for patients with hereditary angioedema caused by a deficiency of C1-Inh [3].
  • However, inactivation of C1-Inh occurs locally in inflamed tissues by proteolytic enzymes (e.g., elastase) released from activated neutrophils or bacteria thereby leading to increased local activation of the various host defense systems [3].
  • C1-Inh, belonging to the superfamily of serine proteinase inhibitors (serpins), is a major inhibitor of the classical complement pathway, the contact activation system, and the intrinsic pathway of coagulation, respectively [3].
  • Likewise, C1-Inh leads to C1q remaining on the immune complex to interact with the C1q receptor [8].

Chemical compound and disease context of SERPING1

  • Heterozygosity for C1INH deficiency results in hereditary angioedema, which is mediated by bradykinin [9].
  • During attacks of angioedema, together with decreasing levels of C1INH, the complement and contact systems are activated: C2 and C4 levels fall and high molecular weight kininogen is cleaved [10].
  • Hereditary angioedema (HAE), characterized by recurrent episodes of angioedema involving the skin, or the mucosa of the upper respiratory or the gastrointestinal tracts, results from heterozygosity for deficiency of the serine proteinase inhibitor (serpin), C1 inhibitor (C1INH) [10].
  • Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema [11].
  • We purified A. hydrophila TagA as a histidine-tagged fusion protein (rTagA) from E. coli DE3 strain using a T7 promoter-based pET30 expression vector and nickel affinity column chromatography. rTagA cleaved C1-INH in a time-dependent manner [12].

Biological context of SERPING1

  • Hybridization of the same blot with three different fragments of the full-length cDNA suggested that exon VII and portions of both flanking introns were deleted in the C1 INH gene [13].
  • The molecular genetic basis of C1 inhibitor (C1 INH) deficiency in a patient with type I hereditary angioneurotic edema was studied [13].
  • Restriction fragment length polymorphism of the C1 INH gene was detected by Southern blot analysis of the patient's DNA after digestion with Pst I or Sac I, and hybridization with a full-length C1 INH cDNA [13].
  • The deletion in the unique N-terminal domain results in a "multimerization phenotype" of C1-Inh, because of diminished stability of the central beta-sheet [14].
  • The data support the hypothesis that C1INH plays a direct role in leukocyte-endothelial cell adhesion, that the activity is mediated by carbohydrate, and that it is independent of protease inhibitory activity [9].

Anatomical context of SERPING1

  • Northern blot analysis of RNA from cultured monocytes, using a probe corresponding to exon VII, also indicated that the abnormal C1 INH mRNA had a deletion of these nucleotides [13].
  • Treatment with plasma C1INH is effective not only in patients with hereditary angioedema, but also in a variety of other disease models, in which such therapy is accompanied by diminished neutrophil infiltration [9].
  • Here we show that both native C1INH and reactive center cleaved C1INH significantly inhibit selectin-mediated leukocyte adhesion in several in vitro and in vivo models, whereas N-deglycosylated C1INH loses such activities [9].
  • Indeed we have found that the C1-INH polypeptide precursor synthesized in a cell-free system is a 64-kDa protein, hence it exceeds the length of the precursor forms of typical serpins [15].
  • Indeed, removal of StcE abolishes the ability of C1-INH to bind erythrocyte surfaces, whereas the proteolysis of C1-INH is unnecessary to potentiate its inhibitory activity [4].

Associations of SERPING1 with chemical compounds

  • When Hageman factor was exposed to a negatively charged surface, provided by either a glass cuvette or dextran sulfate, the addition of C1 INH gave a dose-dependent inhibition of the activity observed [16].
  • However, SDS polyacrylamide gel electrophoresis of the incubation mixture revealed that HF autodigestion had occurred by 48 hours despite the presence of C1 INH [16].
  • This phenotype, as well as the location of the disulfide bridges between the serpin and the non-serpin domain of C1-Inh, suggests that the function of the N-terminal region may be similar to one of the effects of heparin in antithrombin III, maintenance of the metastable serpin conformation [14].
  • C1 inhibitor (C1INH), a member of the serine proteinase inhibitor (serpin) family, is an inhibitor of proteases in the complement system, the contact system of kinin generation, and the intrinsic coagulation pathway [17].
  • The present studies test the hypothesis that plasma C1INH bears sialyl Lewis(x)-related moieties and therefore binds to selectin adhesion molecules [17].

Physical interactions of SERPING1


Regulatory relationships of SERPING1


Other interactions of SERPING1

  • C1-inhibitor (C1-Inh) is a serine protease inhibitor (serpin) with a unique, non-conserved N-terminal domain of unknown function [14].
  • The nature of the proteinase-C1 Inh link was investigated [25].
  • Following preliminary steps to remove plasminogen, fibrinogen, and aggregated material, three conventional chromatographic steps are used to isolate C1-INH in high (70%) overall yield [26].
  • Nucleotide sequence analysis of a clone covering the carboxyterminal half of C1-INH conclusively documents the relatedness of this protein with the serpins, and reveals 27% amino acid identity with alpha 1-antitrypsin [15].
  • However, in the presence of heparin (1 or 50 U/mL), C1Inh appeared to be the major inhibitor of FXIa, followed by ATIII [27].

Analytical, diagnostic and therapeutic context of SERPING1


  1. C1 inhibitor gene expression in patients with hereditary angioedema: quantitative evaluation by means of real-time RT-PCR. Pappalardo, E., Zingale, L.C., Cicardi, M. J. Allergy Clin. Immunol. (2004) [Pubmed]
  2. Mutation screening of the C1 inhibitor gene among Hungarian patients with hereditary angioedema. Kalmár, L., Bors, A., Farkas, H., Vas, S., Fandl, B., Varga, L., Füst, G., Tordai, A. Hum. Mutat. (2003) [Pubmed]
  3. C1-Esterase inhibitor: an anti-inflammatory agent and its potential use in the treatment of diseases other than hereditary angioedema. Caliezi, C., Wuillemin, W.A., Zeerleder, S., Redondo, M., Eisele, B., Hack, C.E. Pharmacol. Rev. (2000) [Pubmed]
  4. Potentiation of C1 esterase inhibitor by StcE, a metalloprotease secreted by Escherichia coli O157:H7. Lathem, W.W., Bergsbaken, T., Welch, R.A. J. Exp. Med. (2004) [Pubmed]
  5. Endotoxin-induced pulmonary dysfunction is prevented by C1-esterase inhibitor. Guerrero, R., Velasco, F., Rodriguez, M., Lopez, A., Rojas, R., Alvarez, M.A., Villalba, R., Rubio, V., Torres, A., del Castillo, D. J. Clin. Invest. (1993) [Pubmed]
  6. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Ennis, S., Jomary, C., Mullins, R., Cree, A., Chen, X., Macleod, A., Jones, S., Collins, A., Stone, E., Lotery, A. Lancet. (2008) [Pubmed]
  7. An IgG autoantibody which inactivates C1-inhibitor. Jackson, J., Sim, R.B., Whelan, A., Feighery, C. Nature (1986) [Pubmed]
  8. Control of the complement system. Liszewski, M.K., Farries, T.C., Lublin, D.M., Rooney, I.A., Atkinson, J.P. Adv. Immunol. (1996) [Pubmed]
  9. A direct role for C1 inhibitor in regulation of leukocyte adhesion. Cai, S., Dole, V.S., Bergmeier, W., Scafidi, J., Feng, H., Wagner, D.D., Davis, A.E. J. Immunol. (2005) [Pubmed]
  10. The pathophysiology of hereditary angioedema. Davis, A.E. Clin. Immunol. (2005) [Pubmed]
  11. Five novel mutations in the C1 inhibitor gene (C1NH) leading to a premature stop codon in patients with type I hereditary angioedema. Freiberger, T., Kolárová, L., Mejstrík, P., Vyskocilová, M., Kuklínek, P., Litzman, J. Hum. Mutat. (2002) [Pubmed]
  12. Molecular and functional characterization of a ToxR-regulated lipoprotein from a clinical isolate of Aeromonas hydrophila. Pillai, L., Sha, J., Erova, T.E., Fadl, A.A., Khajanchi, B.K., Chopra, A.K. Infect. Immun. (2006) [Pubmed]
  13. Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon. Ariga, T., Igarashi, T., Ramesh, N., Parad, R., Cicardi, M., Davis, A.E. J. Clin. Invest. (1989) [Pubmed]
  14. The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant. Bos, I.G., Lubbers, Y.T., Roem, D., Abrahams, J.P., Hack, C.E., Eldering, E. J. Biol. Chem. (2003) [Pubmed]
  15. Molecular cloning of human C1 inhibitor: sequence homologies with alpha 1-antitrypsin and other members of the serpins superfamily. Tosi, M., Duponchel, C., Bourgarel, P., Colomb, M., Meo, T. Gene (1986) [Pubmed]
  16. The effect of C1 inhibitor upon Hageman factor autoactivation. Weiss, R., Silverberg, M., Kaplan, A.P. Blood (1986) [Pubmed]
  17. Complement regulatory protein C1 inhibitor binds to selectins and interferes with endothelial-leukocyte adhesion. Cai, S., Davis, A.E. J. Immunol. (2003) [Pubmed]
  18. Primary structure of the reactive site of human C1-inhibitor. Salvesen, G.S., Catanese, J.J., Kress, L.F., Travis, J. J. Biol. Chem. (1985) [Pubmed]
  19. Characterization of C1 inhibitor binding to neutrophils. Chang, N.S., Boackle, R.J., Leu, R.W. Immunology (1991) [Pubmed]
  20. Detection of activation of the contact system of coagulation in vitro and in vivo: quantitation of activated Hageman factor-C-1-inhibitor and kallikrein-C-1-inhibitor complexes by specific radioimmunoassays. Nuijens, J.H., Huijbregts, C.C., Cohen, M., Navis, G.O., de Vries, A., Eerenberg, A.J., Bakker, J.C., Hack, C.E. Thromb. Haemost. (1987) [Pubmed]
  21. Human C1 esterase inhibitor attenuates murine mesenteric ischemia/reperfusion induced local organ injury. Karpel-Massler, G., Fleming, S.D., Kirschfink, M., Tsokos, G.C. J. Surg. Res. (2003) [Pubmed]
  22. Phosphatase 2A participates in interferon-gamma's induced upregulation of C1 inhibitor mRNA expression. Heda, G.D., Kehoe, K.J., Mahdi, F., Schmaier, A.H. Blood (1996) [Pubmed]
  23. Anti-ischemia/reperfusion of C1 inhibitor in myocardial cell injury via regulation of local myocardial C3 activity. Fu, J., Lin, G., Zeng, B., Wu, Z., Wu, Y., Chu, H., Qin, G., Liang, G., Li, J., Gan, X., Yu, X., Li, C., Liu, D. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  24. C4-binding protein prevents spontaneous cleavage of C3 in sera of patients with hereditary angioedema. Gronski, P., Bodenbender, L., Kanzy, E.J., Seiler, F.R. Complement (1988) [Pubmed]
  25. Fluid-phase interaction of C1 inhibitor (C1 Inh) and the subcomponents C1r and C1s of the first component of complement, C1. Chesne, S., Villiers, C.L., Arlaud, G.J., Lacroix, M.B., Colomb, M.G. Biochem. J. (1982) [Pubmed]
  26. Human C1 inhibitor: improved isolation and preliminary structural characterization. Harrison, R.A. Biochemistry (1983) [Pubmed]
  27. Inactivation of factor XIa in human plasma assessed by measuring factor XIa-protease inhibitor complexes: major role for C1-inhibitor. Wuillemin, W.A., Minnema, M., Meijers, J.C., Roem, D., Eerenberg, A.J., Nuijens, J.H., ten Cate, H., Hack, C.E. Blood (1995) [Pubmed]
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