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Hereditary Angioedema due to C1 inhibitor deficiency: characterization of mutations on SERPING1 gene, clinical correlations and investigation of ancestry

Grant number: 14/26693-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): June 01, 2015
Effective date (End): October 31, 2019
Field of knowledge:Health Sciences - Medicine
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Luisa Karla de Paula Arruda
Grantee:Luana Sella Motta Maia
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):17/18669-5 - Genotype-phenotype correlations in patients with hereditary angioedema, BE.EP.DR

Abstract

Hereditary angioedema (HAE) is a rare disease with autosomal dominant inheritance, characterized by recurrent attacks of subcutaneous edema of upper airways and gastrointestinal tract. In its classic form, the HAE is caused by mutations in SERPING1 gene encoding the C1 inhibitor (C1-INH). HAE Type I results from the quantitative deficiency of C1-INH, whereas HAE type II is characterized by decreased functional activity of C1-INH. More than 240 mutations have been described in SERPING1 gene in patients with HAE. Recently it was described the HAE with normal level of C1-INH, characterized by normal functional and activity of C1-INH and clinical presentation similar to HAE types I and II. In a subgroup of HAE patients with normal C1-INH, mutations were detected in the F12 gene encoding the coagulation factor XII (FXII). The pathogenesis of HAE involves the activation of the kallikrein-kinin pathway, with increased production of bradykinin, a potent vasodilator that leads to angioedema. The diagnosis of HAE is established by characteristic symptoms and clinical tests for complement components. However, systematic analysis of mutations in the SERPING1 gene has been performed in a series of cases of HAE in countries around the world. Although the determination of mutation in C1-INH encoding gene is not essential for the diagnosis of HAE, genetic analysis can provide several benefits, including to allow the early diagnosis of HAE, representing valuable tool for the prevention and early treatment of acute attacks and life-threatening angioedema; to allow the diagnosis of HAE in children during the first year of age, when C1-INH plasma levels may be falsely low; to distinguish from acquired angioedema due CI-INH deficiency; to eliminate the concern of developing the disease or transfer a disease-causing mutation to their progeny. As an almost unknown disease and for its clinical similarity with allergic conditions, HAE is often underdiagnosed. The objectives of this project are: 1. To identify and characterize mutations in SERPING1 gene in patients with HAE types I and II; 2. Correlate mutations found with the clinical characteristics of patients; 3. Analyze and correlate the changes to the ancestry of patients; 4. Standardize the next-generation sequencing to detect mutations in SERPING1 gene for quick and accurate diagnosis of HAE. (AU)