Inherited arrhythmias: from gene variants to ionic channel dysfunctions
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| Year of publication | 2022 |
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| Citation | |
| Description | Inherited arrhythmias represent relatively rare, but life-threatening cardiac pathologies. The origin of the arrhythmias is heterogeneous. Variants in genes encoding cardiac ionic channels or associated proteins can be often detected. A complex clinical, genetic, and functional analysis is then needed to reveal if the identified genetic variant may cause the phenotype. The long QT syndrome (LQTS), the most frequent type of inherited arrhythmia, is associated with various genetic variants, most often in the KCNQ1 gene (LQTS type 1, LQT1). This gene encodes the pore-forming subunit (Kv7.1) of slow delayed rectifier K+ (IKs) channels. We have recently characterized IKs dysfunction caused by two LQT1 variants identified in the Czech population, T309I and R562S. T309I resulted in a complete loss of function due to an impaired channel trafficking in the homozygous setting and a dominant-negative effect in the heterozygous setting (representing the situation in heterozygous carriers). R562S showed a preserved channel trafficking and, in the heterozygous setting, haploinsufficiency. The responsiveness to beta-adrenergic stimulation, an important regulator of IKs channel function namely at an increased sympathetic tone (e.g., at exercise), was preserved in T309I channels whereas it was completely missing in R562S channels. Using in silico simulations in the human ventricular cell model, delayed afterdepolarizations were detected as the possible arrhythmogenic mechanism in both variants. Variants in various genes encoding cardiac ionic channels can be also detected in some patients with idiopathic ventricular fibrillation (VF; both structural heart disease and any clinical signs of an inherited arrhythmia are missing). We have recently selected several identified genetic variants in our patients with idiopathic VF for the functional analysis. Patient-specific cardiomyocytes carrying a variant in the RYR2 gene (Y4734C) were prepared and a pilot investigation has been started (patch-clamp and microelectrode array). The first data showed an increased tendency of the patient-specific cardiomyocytes to irregular electric activity at specific conditions (e.g., increased temperature, decreased extracellular K+ concentration, activation of adrenergic receptors). Ongoing detailed analysis is aimed at elucidating the origin of the proarrhythmic activity in the patient. The connection between genotype, clinical phenotype, and subcellular and cellular origin of the dysfunction is relatively clear in the “classic” inherited arrhythmias. In contrast, idiopathic VF is characterized by the absence of any typical clinical phenotype. Hence, ionic channel dysfunction resulting from an identified associated genetic variant is likely masked by compensatory mechanisms and can be revealed only under specific circumstances. Functional analysis of these variants is essential for a better understanding of the pathophysiology of this life-threatening disease. |
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