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.

The role of the M-band myomesin proteins in muscle integrity and cardiac disease.

Transversal structural elements in cross-striated muscles, such as the M-band or the Z-disc, anchor and mechanically stabilize the contractile apparatus and its minimal unit-the sarcomere. The ability of proteins to target and interact with these structural sarcomeric elements is an inevitable necessity for the correct assembly and functionality of the myofibrillar apparatus. Specifically, the M-band is a well-recognized mechanical and signaling hub dealing with active forces during contraction, while impairment of its function leads to disease and death.

Novel Variant Causing Calmodulinopathy With Variable Expressivity in a 4-Generation Family.

Background: CaM (calmodulin), encoded by 3 separate genes (, , and ), is a multifunctional Ca-binding protein involved in many signal transduction events including ion channel regulation. CaM variants may present with early-onset long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia, or sudden cardiac death. Most reported variants occurred de novo.

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.

A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.

Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly.

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.

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative).

Correlative SICM-FCM reveals changes in morphology and kinetics of endocytic pits induced by disease-associated mutations in dynamin.

Dynamin 2 (DNM2) is a GTP-binding protein that controls endocytic vesicle scission and defines a whole class of dynamin-dependent endocytosis, including clathrin-mediated endocytosis by caveoli. It has been suggested that mutations in the gene, associated with 3 inherited diseases, disrupt endocytosis. However, how exactly mutations affect the nanoscale morphology of endocytic machinery has never been studied.

Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle.

Clathrin plaques are stable features of the plasma membrane observed in several cell types. They are abundant in muscle, where they localize at costameres that link the contractile apparatus to the sarcolemma and connect the sarcolemma to the basal lamina. Here, we show that clathrin plaques and surrounding branched actin filaments form microdomains that anchor a three-dimensional desmin intermediate filament (IF) web.

An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.

Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Ca1.2 have been implicated in arrhythmic syndromes.

Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy.

Rapid advances in allele-specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal-dominant centronuclear myopathy (CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the gene encoding Dynamin 2. Allele-specific siRNA sequences were developed in order to specifically knock down the human and murine -mRNA harbouring the p.

Impaired excitation-contraction coupling in muscle fibres from the dynamin2 mouse model of centronuclear myopathy.

Key Points: Dynamin 2 is a ubiquitously expressed protein involved in membrane trafficking processes. Mutations in the gene encoding dynamin 2 are responsible for a congenital myopathy associated with centrally located nuclei in the muscle fibres. Using muscle fibres from a mouse model of the most common mutation responsible for this disease in humans, we tested whether altered Ca signalling and excitation-contraction coupling contribute to muscle weakness.

Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells.

Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles.

Calcium homeostasis alterations in a mouse model of the Dynamin 2-related centronuclear myopathy.

Autosomal dominant centronuclear myopathy (CNM) is a rare congenital myopathy characterized by centrally located nuclei in muscle fibers. CNM results from mutations in the gene encoding dynamin 2 (DNM2), a large GTPase involved in endocytosis, intracellular membrane trafficking, and cytoskeleton regulation. We developed a knock-in mouse model expressing the most frequent DNM2-CNM mutation; i.

A type 2 ryanodine receptor variant associated with reduced Ca release and short-coupled torsades de pointes ventricular arrhythmia.

Background: Ventricular fibrillation may be caused by premature ventricular contractions (PVCs) whose coupling intervals are <300 ms, a characteristic of the short-coupled variant of torsades de pointes (scTdP).

Objective: The purpose of this study was to analyze the underlying cardiac ryanodine receptor (RyR2) variants in patients with scTdP.

Methods: Seven patients with scTdP (mean age 34 ± 12 years; 4 men and 3 women) were enrolled in this study.

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.

Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins.

The genetics underlying acquired long QT syndrome: impact for genetic screening.

Aims: Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.

Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers).

A Common Mutation of Long QT Syndrome Type 1 in Japan.

Background: Previous studies of long QT syndrome (LQTS) have revealed the presence of country-specific hot spots in KCNQ1 mutations, and the purpose of this study was to evaluate the influence of a common mutation on clinical phenotypes in Japanese LQT1 patients.

Methods and results: We retrospectively studied the frequency of each mutation in 190 LQT1 Japanese probands and evaluated the clinical severity of LQT1 among carriers with a common mutation. We also compared it with that of carriers with other mutations.

Whole-body muscle magnetic resonance imaging in SEPN1-related myopathy shows a homogeneous and recognizable pattern.

Introduction: The aim of this study was to delineate the spectrum of muscle involvement in patients with a myopathy due to mutations in SEPN1 (SEPN1-RM).

Methods: Whole-body magnetic resonance imaging (WBMRI) was used in 9 patients using T1-weighted turbo spin-echo (T1-TSE) sequences and short tau inversion recovery (STIR) in 5 patients.

Results: Analysis of signal and volume abnormalities by T1-TSE sequences in 109 muscles showed a homogeneous pattern characterized by a recognizable combination of atrophy and signal abnormalities in selected muscles of the neck, trunk, pelvic girdle, and lower limbs.

Role of common and rare variants in SCN10A: results from the Brugada syndrome QRS locus gene discovery collaborative study.

Aims: Brugada syndrome (BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction. We aimed to identify genetic variation in BrS cases at loci associated with QRS duration.

Methods And Results: A multi-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%).