Abstract
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.
Highlights
Hereditary angioedema (HAE) is a rare autosomal dominant disease, with an estimated prevalence of one case per 50,000 persons, characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intraabdominal edema [1,2,3,4]
Eleven patients from five families were diagnosed with HAE type I, and six patients from three families with HAE type II
In our cohort of eight Slovenian families with a clinical diagnosis of HAE, mutations in the SERPING1 gene responsible for the disease were identified in all patients from seven families
Summary
Hereditary angioedema (HAE) is a rare autosomal dominant disease, with an estimated prevalence of one case per 50,000 persons, characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intraabdominal edema [1,2,3,4]. In addition to classical pathways, C1 inhibitor controls the lectin complement pathway [1,2]. It controls the mannosebinding protein-associated serine protease system, as well as kallikrein, coagulation factors XIIa and XIa, plasmin, and tissue plasminogen activator [1]. Estrogen-dependent or HAE type III occurs in patients with normal C1 inhibitor level and function. It mainly involves women and the exact mechanism remains unknown, in some patients a mutation in the coagulation factor XII gene have been identified [1,2]
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