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Role of ion channel-interacting proteins in cardiac channelopathies

English title Role of ion channel-interacting proteins in cardiac channelopathies
Applicant Abriel Hugues
Number 128016
Funding scheme SCOPES
Research institution Department for BioMedical Research Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Clinical Cardiovascular Research
Start/End 01.12.2009 - 30.11.2013
Approved amount 185'000.00
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All Disciplines (2)

Clinical Cardiovascular Research
Clinical Pathophysiology

Keywords (6)

ion channels; genetics; electrophysiology; sudden cardiac death; arrhythmias; ion channel

Lay Summary (English)

Lay summary
Sudden cardiac death is a major cause of mortality in industrialized countries. Since now more than 15 years, it is known that dysfunction of ion channels, which are small proteins important for the electrical activity of the heart, may cause fatal cardiac rhythm disturbances (arrhythmias). These human diseases that are caused by malfunction of ion channels are called "channelopathies". In this project, we will investigate new candidate genes that may be mutated in patients with cardiac channelopathies. These patients show severe cardiac arrhythmias, so-called long QT syndrome and Brugada syndrome, at young age, and may die suddenly because of mutations found in genes important for the heart function. The patients will be recruited in Ukraine, Russia, and Switzerland. After informed consent from the patients and their families, several new genes important for the cardiac electric activity will be analysed by the Russian team. The new mutations that will be found will be analysed by the Swiss team. The results of this project will permit 1) to demonstrate the causal relationship between the genetic variants and the pathology of the patients, 2) to perform more precise genetic counselling of the patients and family members, and 3) to better understand the genetic and molecular mechanisms underlying these complex cardiac diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants


Cardiac channelopathies: Genetic and molecular mechanisms
Abriel Hugues, Zaklyazminskaya Elena V. (2013), Cardiac channelopathies: Genetic and molecular mechanisms, in GENE, 517(1), 1-11.
Characterization of 2 Genetic Variants of Na(v)1.5-Arginine 689 Found in Patients with Cardiac Arrhythmias
Sottas Valentin, Rougier Jean-Sebastien, Jousset Florian, Kucera Jan P., Shestak Anna, Makarov Leonid M., Zaklyazminskaya Elena V., Abriel Hugues (2013), Characterization of 2 Genetic Variants of Na(v)1.5-Arginine 689 Found in Patients with Cardiac Arrhythmias, in JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, 24(9), 1037-1046.

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Funding: The Scientific Cooperation Between Eastern Europe and Switzerland Programme Circulation International 2011

Associated projects

Number Title Start Funding scheme
127682 Inherited Channelopathies 01.09.2010 International Exploratory Workshops
147060 Molecular Determinants of Nav1.5 Multiprotein Complexes in Cardiac Cells 01.04.2013 Project funding (Div. I-III)


Background - Recent genetic findings have shown that cardiac ion channel dysfunction plays a central role in the genesis of arrhythmias leading to sudden cardiac death (SCD), defining the field of cardiac genetic channelopathies. The mutations found in these patients are not only in the genes encoding ion channel subunits, but also in genes coding for ion channel-regulatory proteins. Three proteins from the syntrophin family, alpha-1-syntrophin, beta-1-syntrophin, and beta-2-syntrophin, are known to be expressed widely (mainly in neural and muscular tissues) and to be part of dystrophin-associated multiprotein complex. Syntrophins were shown to interact with the carboxy-terminus of the voltage-gated sodium channel Nav1.5; and it was recently reported that mutations in the gene SNTA1, coding for alpha1-syntrophin, can cause congenital Long QT Syndrome (LQTS), the first described syndrome of this group of diseases. Unfortunately, the pathogenetic mechanisms leading to cardiac arrhythmias via alpha-1-syntrophin dysfunction are still not completely understood. Furthermore, two additional syntrophin genes (gamma 1 and 2) were described, SNTG1 and SNTG2, but only SNTG2 is expressed in the heart.In the group of Dr. H. Abriel, it has been recently shown (unpublished data) that Nav1.5 also interacts with a protein called SAP97 (belonging to the family of anchoring MAGUK proteins), and that SAP97 is involved in regulating the membrane density of the Nav1.5 protein at the cell surface. DLG1 is the gene coding for SAP97. Thus far, the genetic polymorphism of these genes as well as their implication in human diseases is still poorly understood. Working Hypothesis - Since mutations in the gene coding for Nav1.5 may lead to a long list of cardiac pathological phenotypes, we postulate that gene variants coding for Nav1.5 associated-proteins may also be responsible for similar diseases. By screening such genes, we expect to find pathogenic genetic variants in SNTA1, SNTB1, SNTB2, and SNTG2, as well as DLG1 genes in patients with Long QT syndrome, Short QT syndrome, Brugada syndrome, Idiopathic ventricular fibrillation or idiopathic dilated cardiomyopathy. Accordingly, the specific aims of this research proposal are:1.To investigate the genetic diversity in syntrophin (SNT1A, SNT1B, SNT2B, SNTG2) genes in patients with cardiac electrical disorders and in healthy controls.2.To investigate the genetic diversity in SAP97 (DLG1) gene in patients with cardiac electrical disorders and in healthy controls.3.To compare the prevalence of the found genetic variants of SNT1A, SNT1B, SNT2B, SNTG2 and DLG1 in different ethnic groups from Russia, Ukraine, and Switzerland.4.To analyze the role of the genetic variants of the syntrophin genes in cellular re-expression experiments.5.To study the role of the genetic variants of the SAP97 gene in cellular re-expression experiments.Experimental Design - In this project, we plan to 1) enroll patients from Ukraine with the mentioned pathological phenotypes (and continue to enroll Swiss and Russian patients); 2) perform genetic analysis of the 5 genes in Moscow; and 3) study the genetic variants found in these genes in Bern.Expected Value of the Project - The findings of this project will permit 1) a better understanding of the roles of these proteins in regulating Nav1.5 in cardiac cells; 2) to demonstrate the roles of these genes in cardiac channelopathies; and 3) a more accurate and effective genetic counseling of patients with cardiac arrhythmias of genetic origin.