Mutational spectrum of the<i> C1INH (SERPING1) </i>gene in patients with hereditary angioedema

Abstract

Hereditary angioedema (HAE) is an autosomal dominant disease that manifests as intermittent acute swellings of the skin and mucosal surfaces, which, in the gastrointestinal tract and larynx, may even be fatal. HAE results from functional deficiency of the C1 inhibitor (C1INH) protein, which plays a key role in the classical pathway of complement activation. C1INH is the sole inhibitor of the activated proteases C1r and C1s, and is the major regulator of activated coagulation Factor XII and plasma kallikrein, which limits the generation of the vasoactive peptide bradykinin. In this paper, we report on the genetic analysis of 173 families (including 326 members) with a clinical diagnosis of HAE. Direct sequencing, Southern blotting and quantitative PCR by the MLPA method were used to screen for mutations in C1INH (SERPING1). In 142 families (82.1%), a causative C1INH gene mutation could be identified. A total of 80 novel point mutations of C1INH not published previously were detected in 96 pedigrees (including 172 members). Our results corroborate C1INH (SERPING1) deficiency as a disease of extreme allelic heterogeneity with almost each individual family carrying their own mutation. Routine molecular genetic analysis is an effective way of confirming the clinical diagnosis and identifying mutation carriers early on before any clinical manifestation becomes apparent. It is, therefore, a valuable tool in prevention and adequate treatment of acute and life-threatening oedema.

Hereditary angioedema with a mutation in the plasminogen gene

“…The presence of HAE‐specific F12 gene mutations and of mutations of the SERPING1 gene was tested as described elsewhere …”

Hereditary angioedema with normal C1‐INH with versus without specific F12 gene mutations

“…HAE‐specific F12 mutations and mutations of the SERPING1 gene were identified as described elsewhere .…”

Hereditary Angioedema in Greece: The First Results of the Greek Hereditary Angioedema Registry

“…In type I HAE (85% of patients), the antigenic concentration of C1-INH is <35% of normal, while in type II HAE (15% of cases) the concentration of C1-INH is found to be normal or even increased but the protein is not active. Genetic defects in the SERPING1 gene, which encodes C1-INH, are responsible for both disease types [4,5]. A third type of HAE usually affects women and is most commonly associated with conditions of elevated estrogen levels (e.g.…”