SERPING1 variant is not secreted

Stable Identifier
Reaction [transition]
Homo sapiens
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C1-esterase inhibitor (serpin G1, C1-INH, SERPING1) is a 105 kDa protease inhibitor which belongs to the serine protease inhibitor (serpin) super family of structurally similar but functionally diverse proteins that use a conformational change to inhibit target enzymes (Silverman GA et al. 2001; Gettins PG 2002; Law RH et al. 2006; Khan MS et al. 2011). SERPING1 inhibits the proteases of the complement system, C1r, C1s and MASP2 by forming stable and enzymatically inactive complexes (Arlaud GJ et al. 1979, Sim RB et al. 1979). Besides complement regulation, SERPING1 controls vascular permeability by inactivating factor XIa (FXIa), FXIIa and plasma kallikrein, the proteases of the contact system involved in bradykinin generation (Schreiber AD et al. 1973; Ravindran S et al. 2004; Kaplan AP & Joseph K 2016). Serpins, including SERPING1, are conformationally labile and many of the disease-linked variants of serpins result in misfolding or in formation of pathogenic, inactive polymers (Law RH et al. 2006; Khan MS et al. 2011; Haslund D ET AL. 2019). Defective SERPING1 (C1 inhibitor deficiency) results in excessive enzyme activity and is linked to hereditary angioedema (HAE), an autosomal dominant disease characterized by recurrent episodes of localized edema of the skin or of the mucosa of the gastrointestinal tract or upper airway (Carugati A et al. 2001; Suffritti C et al. 2014: Zuraw BL & Christiansen SC 2016; Kaplan AP & Joseph K 2016). The edema formation is primarily caused by a transient increased bradykinin release and increased permeability at the level of the postcapillary venule due to uncontrolled activation of the coagulation factor XII (FXII)-dependent kallikrein kinin system (Bossi F et al. 2009; Kaplan AP 2010; Suffritti C et al. 2014: Zuraw BL & Christiansen SC 2016). Although activation of complement does not produce a vasoactive peptide that could be considered to be pathogenic in HAE, the absence of functional SERPING1 causes uncontrolled C1 complex activity with breakdown of C4 and C2 components of complement, which are the natural substrates of C1s. Thus 95 percent of patients with HAE have a low C4 level which allows for rapid diagnosis of HAE caused by defective SERPING1 even if a family history of swelling is not present (Kaplan AP & Joseph K 2016). Based on the relative levels of functional and antigenic SERPING1 (C1-INH), two types of HAE with SERPING1deficiency have traditionally been described. In type I (± 85% of HAE patients with SERPING1deficiency), defective expression of one allele results in low antigenic and functional levels of C1 inhibitor protein. It has been suggested that in patients with type I HAE the disease-linked variants of SERPING1 may cause reduced plasma levels of functional SERPING1 by negatively affecting synthesis, intracellular transport, or secretion of the normal SERPING1(C1-INH) protein (Kramer J et al. 1993; Verpy E et al. 1993; Ernst SC et al. 1996; Haslund D et al. 2019). Further, in a subset of patients with type I HAE, defective SERPING1 variants interacted with wildtype (wt) SERPING1 in a dominant-negative manner and formed intracellular SERPING1 aggregates (Haslund D et al. 2019). These aggregates lead to a reduction in the levels of secreted functional SERPING1. Importantly, in patient-derived fibroblasts, the administration of wild-type SERPING1 gene was able to restore the levels of secreted SERPING1 (C1-INH) protein, suggesting that dominant-negative disease mechanisms can be overcome by gene supplementation (Haslund D et al. 2019). In type II (±15% of HAE patients), levels of functional SERPING1 protein are low, but SERPING1 antigen levels are normal because of the presence of a dysfunctional variant. This classification has however been challenged by observations of intermediary HAE types, that can arise, when a small amount of dysfunctional SERPING1 is present in the blood stream (Eldering E et al. 1995; Verpy E et al. 1995; Madsen DE et al. 2014).

This Reactome event describes defective cellular secretion of SERPING1 variants expressed from alleles identified mostly in patients with HAE type I.

Literature References
PubMed ID Title Journal Year
26248961 F12-46C/T polymorphism as modifier of the clinical phenotype of hereditary angioedema

Speletas, M, Szilágyi, Á, Csuka, D, Koutsostathis, N, Psarros, F, Moldovan, D, Magerl, M, Kompoti, M, Varga, L, Maurer, M, Farkas, H, Germenis, AE

Allergy 2015
30398465 Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema

Haslund, D, Ryø, LB, Seidelin Majidi, S, Rose, I, Skipper, KA, Fryland, T, Bohn, AB, Koch, C, Thomsen, MK, Palarasah, Y, Corydon, TJ, Bygum, A, Nejsum, LN, Mikkelsen, JG

J. Clin. Invest. 2019
29753808 Targeted next-generation sequencing for the molecular diagnosis of hereditary angioedema due to C1-inhibitor deficiency

Loules, G, Zamanakou, M, Parsopoulou, F, Vatsiou, S, Psarros, F, Csuka, D, Porebski, G, Obtulowicz, K, Valerieva, A, Staevska, M, López-Lera, A, López-Trascasa, M, Moldovan, D, Magerl, M, Maurer, M, Speletas, M, Farkas, H, Germenis, AE

Gene 2018
14635117 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
7852321 COOH-terminal substitutions in the serpin C1 inhibitor that cause loop overinsertion and subsequent multimerization

Eldering, E, Verpy, E, Roem, D, Meo, T, Tosi, M

J. Biol. Chem. 1995
29343682 Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight

Caccia, S, Suffritti, C, Carzaniga, T, Berardelli, R, Berra, S, Martorana, V, Fra, A, Drouet, C, Cicardi, M

Sci Rep 2018
7814636 Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function

Verpy, E, Couture-Tosi, E, Eldering, E, López-Trascasa, M, Späth, P, Meo, T, Tosi, M

J. Clin. Invest. 1995
8755917 Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema

Verpy, E, Biasotto, M, Brai, M, Misiano, G, Meo, T, Tosi, M

Am. J. Hum. Genet. 1996
Participant Of
Normal reaction
Name Identifier Synonyms
C1 inhibitor deficiency 0060002 Quincke edema
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