Molecular Biology
and Lysosomal Disease
Diagnosis Laboratory
Center for Research and Diagnosis of Genetic Diseases

Hereditary Angioedema

The Hereditary Angioedema (HAE) (OMIM#106100) is a dominant genetic disease characterized by recurrent episodes of subcutaneous edema that mainly affect the extremities (hands, feet, joints) and face, a gastrointestinal mucosa and can reach the larynx and oropharynx, leading to dilation of the gastrointestinal mucosa and risk of death. People that have quantitative or qualitative deficiency of the C1 inhibitor (C1-INH) due mutations in the gene that codify the inhibitor (SERPING1-NG_009625.1) are carriers of AEH type I and II, respectively. A third kind of HAE in which patients present normal C1-INH was associate to mutations in the coding gene of FXII (F12-NG_007568.1). There are a group of patients with HAE without deficiency in C1-INH or mutation in F12, with genetic cause unknown.

The C1-INH is the main physiological regulator of the Kalicrein-Kinins plasmatic system activity in humans, that starts by the activation of FXII and culminates in the release of the non-vasodilator and pro-inflammatory bradykinin (BK). Once C1-INH deficiency or facilitation of FXII activation occurs, excessive release of BK occurs, leading to increased vascular permeability and extravasation of fluid into the submucosal and sucutaneous tissues that are characteristic of angioedema.

Patient-to-patient variation can be extreme, even among individuals from the same family (with the same causative mutation), and although the genetic cause of the disease is identified, the factors that modulate this variation are unknown.

Thus, the objectives of this project are to study genetic characteristics in patients with HAE that may influence the variation of symptoms, focusing on genes directly related to the BK release pathway; in addition to performing the precise molecular diagnosis of each patient and better understand the relation of the identified mutations and the protein function of C1-INH and FXII.

This project had the financial support of FAPESP (regular project 2013/02661-4; 2013-2015) and comprises one of the subprojects of the Thematic Project "Establishment of a genetic and molecular research center for clinical challenges" (2014 / 27198-8; 2016-2020). PhD students Nathália Cagini (FAPESP scholarship 14 / 01544-7) and Rafael Filippelli da Silva (CAPESP scholarship) and postdoctoral students Camila Lopes Veronez (scholarship FAPESP 15 / 25494-1) and Renan Paulo Martin (FAPESP scholarship 14 / 20965-3).

 

Publications:

 

Veronez CL, da Silva ED, Lima Teixeira PV, Cagini N, Constantino-Silva RN, Grumach AS, Mansour E, Velloso LA, Pesquero JB. Genetic analysis of hereditary angioedema in a Brazilian family by targeted next generation sequencing. Biol Chem. 2016 Apr;397(4):315-22. doi: 10.1515/hsz-2015-0212.

 

Cagini N, Veronez CL, Constantino-Silva RN, Buzolin M, Martin RP, Grumach AS, Velloso LA, Mansour E, Pesquero JB. New mutations in SERPING1 gene of Brazilian patients with hereditary angioedema. Biol Chem. 2016 Apr;397(4):337-44. doi: 10.1515/hsz-2015-0222.

 

Grumach AS, Stieber C, Veronez CL, Cagini N, Constantino-Silva RN, Cordeiro E, Nöthen MM, Pesquero JB, Cichon S. Homozygosity for a factor XII mutation in one female and one male patient with hereditary angio-oedema.Allergy. 2016 Jan;71(1):119-23. doi: 10.1111/all.12769.

 

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