Defective SERPING1 causes hereditary angioedema

Stable Identifier
Homo sapiens
Defective C1 inhibitor causes hereditary angioedema
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The reciprocal activation is initiated when zymogen factor XII (F12 or FXII) binds to a negatively charged surface, which induces FXII autoactivation. Activated FXII (FXIIa) converts prekallikrein (PK) to kallikrein, which proteolytically liberates bradykinin from high molecular weight kininogen (HK) (Renne T 2012; Renne T et al. 2012; Maas C et al. 2011). Kallikrein also activates FXII to produce more FXIIa (initially). FXIIa and kallikrein reciprocally activate their zymogens and thus generate a positive feedback loop. In the presence of sufficient amounts of active enzyme, FXIIa also generates active factor XI (FXIa) to potentiate the intrinsic coagulation pathway. All of these enzymatic steps are normally inhibited by C1-esterase inhibitor (C1-INH, encoded by the SERPING1 gene).

Binding of the proinflammatory peptide hormone bradykinin to the bradykinin B2 receptor (B2R) activates various proinflammatory signaling pathways that increase vascular permeability and fluid efflux. An excessive formation of bradykinin due to uncontrolled activation of the coagulation factor XII (FXII)-dependent kallikrein-kinin system causes increased vascular permeability at the level of the postcapillary venule and results in hereditary angioedema (HAE) (Bossi F et al. 2009; Kaplan AP 2010; Suffritti C et al. 2014: Zuraw BL & Christiansen SC 2016). HAE is a rare life-threatening inherited edema disorder that is characterized by recurrent episodes of localized edema of the skin or of the mucosa of the gastrointestinal tract or upper airway. Angioedema initiated by bradykinin is usually associated with SERPING1 (C1-INH) deficiency. Thus, a major role of SERPING1 (C1-INH) is to prevent the development of excessive vascular permeability. More rarely, HAE occurs in individuals with normal SERPING1 activity, linked to mutations in other proteins, including FXII, plasminogen, and angiopoietin (Magerl M et al. 2017; Zuraw BL 2018; Ivanov I et al. 2019). Patients with HAE are heterozygous for deficiency of SERPING1.The disease, therefore, has an autosomal dominant inheritance and may result from lack of expression of SERPING1 from one allele (type 1 HAE) or from expression of a nonfunctional SERPING1 protein (type 2 HAE). This classification has however been challenged by observations of intermediary HAE types, that can arise, when small amounts of dysfunctional SERPING1 is present in the blood stream (Eldering E et al. 1995; Verpy E et al. 1995; Madsen DE et al. 2014).

Literature References
PubMed ID Title Journal Year
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
2563376 CpG mutations in the reactive site of human C1 inhibitor

Skriver, K, Radziejewska, E, Silbermann, JA, Donaldson, VH, Bock, SC

J. Biol. Chem. 1989
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
29920929 Hereditary angioedema: the plasma contact system out of control

De Maat, S, Hofman, ZLM, Maas, C

J. Thromb. Haemost. 2018
24552232 High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency

Suffritti, C, Zanichelli, A, Maggioni, L, Bonanni, E, Cugno, M, Cicardi, M

Clin. Exp. Allergy 2014
8798678 Characterization of C1 inhibitor-Ta. A dysfunctional C1INH with deletion of lysine 251

Zahedi, R, Aulak, KS, Eldering, E, Davis, AE

J. Biol. Chem. 1996
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
8529136 A mutation unique in serine protease inhibitors (serpins) identified in a family with type II hereditary angioneurotic edema

Ocejo-Vinyals, JG, Leyva-Cobián, F, Fernández-Luna, JL

Mol. Med. 1995
1451784 A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444-->Leu)

Frangi, D, Aulak, KS, Cicardi, M, Harrison, RA, Davis, AE

FEBS Lett. 1992
Participant Of
Name Identifier Synonyms
hereditary angioedema 14735 HANE, Hereditary angioedema, Hereditary angioneurotic edema
C1 inhibitor deficiency 0060002 Quincke edema
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