Intracardiac electrophysiology to characterize susceptibility to ventricular arrhythmias in murine models.

Sudden cardiac death (SCD) and ventricular fibrillation are rare but severe complications of many cardiovascular diseases and represent a major health issue worldwide. Although the primary causes are often acute or chronic coronary diseases, genetic conditions, such as inherited channelopathies or non-ischemic cardiomyopathies are leading causes of SCD among the young. However, relevant experimental models to study the underlying mechanisms of arrhythmias and develop new therapies are still needed.

Trafficking and Gating Cooperation Between Deficient Na1.5-mutant Channels to Rescue I.

Background: Pathogenic variants in , the gene encoding the cardiac Na+ channel α-subunit Nav1.5, result in life-threatening arrhythmias, e.g.

Generation of a heterozygous SCN5A knockout human induced pluripotent stem cell line by CRISPR/Cas9 edition.

Mutations leading to haploinsufficiency in SCN5A, the gene encoding the cardiac sodium channel Na1.5 α-subunit, are involved in life-threatening cardiac disorders. Using CRISPR/Cas9-mediated genome edition, we generated here a human induced-pluripotent stem cell (hiPSC) line carrying a heterozygous mutation in exon 2 of SCN5A, which leads to apparition of a premature stop codon.

A Type 2 Ryanodine Receptor Variant in the Helical Domain 2 Associated with an Impairment of the Adrenergic Response.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered by exercise or acute emotion in patients with normal resting electrocardiogram. The major disease-causing gene is , encoding the cardiac ryanodine receptor (RyR2). We report a novel variant, p.

Dominant-Negative Effect of an Brugada Syndrome Variant.

Unlabelled: Loss-of-function mutations in the cardiac Na channel α-subunit Na1.5, encoded by , cause Brugada syndrome (BrS), a hereditary disease characterized by sudden cardiac death due to ventricular fibrillation. We previously evidenced the dominant-negative effect of the BrS Na1.

Inter-Regulation of K4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies.

Background: Genetic variants in voltage-gated sodium channels (Na) encoded by genes, responsible for I, and K4.3 channels encoded by , responsible for the transient outward current (I), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that K4.

A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions.

Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM.

A truncating SCN5A mutation combined with genetic variability causes sick sinus syndrome and early atrial fibrillation.

Background: Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na(+) channel, Nav1.5, can result in several life-threatening arrhythmias.

Objective: To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block.

Desmosomal cadherins are decreased in explanted arrhythmogenic right ventricular dysplasia/cardiomyopathy patient hearts.

Aims: Arrhythmogenic right ventricular Dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited cardiomyopathy associated with ventricular arrhythmia, heart failure and sudden death. Genetic studies have demonstrated the central role of desmosomal proteins in this disease, where 50% of patients harbor a mutation in a desmosmal gene. However, clinical diagnosis of the disease remains difficult and molecular mechanisms appears heterogeneous and poorly understood.

Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Na(v)1.5 α-subunits.

Aims: Brugada syndrome (BrS) is an autosomal-inherited cardiac arrhythmia characterized by an ST-segment elevation in the right precordial leads of the electrocardiogram and an increased risk of syncope and sudden death. SCN5A, encoding the cardiac sodium channel Na(v)1.5, is the main gene involved in BrS.

MOG1: a new susceptibility gene for Brugada syndrome.

Background: Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes.

Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes.

Membrane-associated guanylate kinase (MAGUK) proteins are major determinants of the organization of ion channels in the plasma membrane in various cell types. Here, we investigated the interaction between the MAGUK protein SAP97 and cardiac Kv4.2/3 channels, which account for a large part of the outward potassium current, I(to), in heart.

The anchoring protein SAP97 retains Kv1.5 channels in the plasma membrane of cardiac myocytes.

Membrane- associated guanylate kinase proteins (MAGUKs) are important determinants of localization and organization of ion channels into specific plasma membrane domains. However, their exact role in channel function and cardiac excitability is not known. We examined the effect of synapse-associated protein 97 (SAP97), a MAGUK abundantly expressed in the heart, on the function and localization of Kv1.

Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.

Aims: Idiopathic dilated cardiomyopathy (DCM) is a cardiac disorder characterized by left ventricular dilatation and impaired systolic contraction. It is a major cause of heart failure and heart transplantation. DCM is of genetic origin in approximately 30% of cases and genetically heterogeneous with the identification of numerous disease genes.

Heart rate influences on repolarization duration and morphology in symptomatic versus asymptomatic KCNQ1 mutation carriers.

QT and Tp/Te intervals were longer in patients with LQT1 (n = 67) than in nonaffected subjects (n = 52) but did not differentiate symptomatic (n = 21) from asymptomatic patients (n = 46). At fast heart rate, the time to accumulate the last part of total T-wave area (the t50-97 interval) was longer in symptomatic carriers compared with asymptomatic patients (119 +/- 19 vs 106 +/- 15 ms, p <0.01).

[MAGUKs: beyond ionic channel anchoring].

A family of anchoring proteins named MAGUK (for membrane associated guanylate kinase) has emerged as a key element in the organization of protein complexes in specialized membrane regions. These proteins are characterized by the presence of multipe protein-protein interaction domains including PDZ and SH3 domains. The MAGUK family comprises the post-synaptic density 95 (PSD-95) protein and closely related molecules such as chapsyn-110, synapse-associated protein 102 (SAP-102), and SAP-97.

Isoform-specific modulation of voltage-gated Na(+) channels by calmodulin.

Calmodulin (CaM) is a calcium-sensing protein that binds to Na(+) channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (micro1) but not cardiac (hH1) Na(+) channels. Mutant CaM(1234) did not alter the voltage dependence or the kinetics of gating of either micro1 or hH1.