The effect of sequence variations within the coding region of the C1 inhibitor gene on disease expression and protein function in families with hereditary angio-oedema

Cumming, S.-A.; Halsall, DJ; Ewan, P.; Lomas, DA

doi:10.1136/jmg.40.10.e114

Cited by 40 publications

(47 citation statements)

References 24 publications

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“…She was also supplied with C1 inhibitor concentrate and responded well to the administration during angioedema attacks. Variant c.-21T>C is the second nucleotide of exon 2, located in the non-translated region; it is part of the canonical acceptor site and may affect message splicing but not protein structure [8], [27]. This change was previously referred to as a non-pathogenic polymorphism in heterozygous form [8], [13], [16], [19], but might be pathogenic in homozygous form [22].…”

Section: Discussionmentioning

confidence: 99%

Hereditary Angioedema Nationwide Study in Slovenia Reveals Four Novel Mutations in SERPING1 Gene

et al. 2013

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Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE) or normal levels of ineffective C1 inhibitor (Type II HAE). A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function), followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T) and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T), and Glu429Lys (c.1351G>A), together with two frameshift mutations, indel (c.49delGinsTT) and deletion (c.593_594delCT). Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T) and Arg444His (c.1397G>A), respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C) was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C) might be responsible for the disease.

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Section: Discussionmentioning

confidence: 99%

Hereditary Angioedema Nationwide Study in Slovenia Reveals Four Novel Mutations in SERPING1 Gene

et al. 2013

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“…Only a few HAE severity score systems exist and there does not seem to be consensus on which provides the best data (10,11). It has previously been shown that early onset of symptoms is associated with a more severe cause of disease (2,12).…”

Section: Health-related Quality Of Life In Danish Patients With Heredmentioning

confidence: 98%

Health-related Quality of Life in Danish Patients with Hereditary Angioedema

Aabom

Andersen²,

Pérez‐Fernández

et al. 2015

Acta Derm Venerol

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“…Replacement of valine 458 by methionine is a common polymorphism with an allele frequency of 31% in the healthy population (Bock et al, 1986;Cumming et al, 2003) but the relevance of this mutation for C1INH activity has to be proven by future expression studies.…”

Section: Discussionmentioning

confidence: 99%

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

Göβwein

Kocot

Emmert

et al. 2008

Cytogenet Genome Res

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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.

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The effect of sequence variations within the coding region of the C1 inhibitor gene on disease expression and protein function in families with hereditary angio-oedema

Cited by 40 publications

References 24 publications

Hereditary Angioedema Nationwide Study in Slovenia Reveals Four Novel Mutations in SERPING1 Gene

Hereditary Angioedema Nationwide Study in Slovenia Reveals Four Novel Mutations in SERPING1 Gene

Health-related Quality of Life in Danish Patients with Hereditary Angioedema

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

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