Biology subjects

Paasche, A.

Publications and source records attributed to Paasche, A..

3 recordsLinked to original sources

bioRxiv2026

Beta-Adrenergic Stimulation and MYH7 G256E Mutant Gene Dosage Drive Hypertrophic Cardiomyopathy Phenotype Penetrance

AimsHypertrophic cardiomyopathy (HCM) is the most prevalent genetic heart disorder, characterized by significant phenotypic variability even among individuals with identical MYH7 mutations. This study aims to elucidate factors contributing to this variability and identify drivers of phenotype penetrance. We compared the baseline phenotypes of a highly penetrant MYH7 H251N mutation and the variably penetrant MYH7 G256E mutation and investigated the impact of adding beta-adrenergic stimulation and homozygosity on disease phenotype penetrance using cardiomyocytes from an isogenic line of human induced pluripotent stem cells (hiPSC-CMs). Methods and ResultsIsogenic hiPSCs with MYH7 H251N and MYH7 G256E mutations were generated using CRISPR/Cas9 technology and differentiated into cardiomyocytes (CMs). Single-cell RNA sequencing (scRNAseq) and functional analysis of contractile function revealed consistent HCM phenotype presentation in H251N CMs, whereas G256E CMs exhibited a subtle and more variable phenotype. Beta-adrenergic stimulation induced a distinct metabolic stress response in G256E CMs, characterized by impaired mitochondrial ATP upregulation. Increasing mutant gene dosage from hetero- to homozygosity led to consistent increase in hypertrophic and structural gene expression changes in G256E CMs at RNA and protein levels. These changes were distinct from the changes observed with stress response. Importantly, homozygous G256E CMs exhibited a hypercontractile functional and disorganized structural phenotype. Across multiple experimental conditions, we identified consistent increase in cardiomyocyte specific transcriptomic markers such as NPPB, APOE, PDLIM3 and ANKRD1. ConclusionsOur study highlights the use of a variably penetrant MYH7 mutation to investigate factors that influence HCM phenotype penetrance. Specifically, we found that mutant gene dosage and beta-adrenergic stimulation induce distinct HCM disease phenotypes, providing novel insights into mechanisms that may contribute to variable disease expression in HCM. Translational PerspectiveHCM is characterized by significant phenotypic variability, complicating both diagnosis and clinical management. This study explores the factors driving HCM phenotype penetrance using isogenic hiPSC-CMs with MYH7 mutations. We demonstrate that beta-adrenergic stimulation and increased mutant gene dosage significantly impact HCM disease penetrance. Beta-adrenergic stimulation triggers metabolic stress responses, while increased gene dosage leads to a hypercontractile and structurally disorganized phenotype. These findings provide insight into how specific modifiers can shape disease-associated phenotypes in HCM model systems. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/729411v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@16a72d7org.highwire.dtl.DTLVardef@1999ca6org.highwire.dtl.DTLVardef@1fb8752org.highwire.dtl.DTLVardef@7148b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Disruption of RBM20 causes atrial electrophysiological disturbances

BackgroundDilated cardiomyopathy (DCM) is a leading cause of heart failure, with 30-50 % of cases attributed to familial inheritance. Mutations in RNA-binding motif protein 20 (RBM20) account for 3-5 % of cases and are associated with severe DCM and ventricular arrhythmias. However, the role of RBM20 mutations in atrial cardiomyopathy (AtCM) and atrial fibrillation (AF) remains underexplored. This study investigates the effects of the RBM20-R636Q mutation on atrial electrophysiology and evaluates sodium-glucose co-transporter (SGLT) inhibitors as potential therapeutics. ResultsRbm20-R636Q mice exhibited atrial remodeling, including hypertrophy, left atrial enlargement, and shortened action potential duration at 90% repolarization (APD90). Compared with RBM20-knockout and laminopathy models, RBM20-R636Q mice showed distinct reductions in Ito / IKur without changes in IK,sus or IK,tail currents, alongside TASK-1 potassium current upregulation and alterations of ICaL. SGLT inhibitors (sotagliflozin, empagliflozin, dapagliflozin) reduced AP inducibility and partially restored APD90, with effects comparable to lidocaine, suggesting a role in modulating peak sodium currents. ConclusionsRBM20 mutations contribute to atrial remodeling, promoting AtCM and AF. SGLT inhibitors demonstrate therapeutic potential by modulating atrial electrophysiology and reducing arrhythmogenesis, offering a promising strategy for managing RBM20-related cardiac disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/711772v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@7bcccaorg.highwire.dtl.DTLVardef@1c20b0dorg.highwire.dtl.DTLVardef@63bbcdorg.highwire.dtl.DTLVardef@1bea67f_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Transcriptional regulation of the TASK-1 potassium channel by ETV1 -Implications for atrial excitability

BackgroundAtrial fibrillation (AF), the most common sustained arrhythmia, is driven by electrical and structural remodelling, including altered ion channel expression. The atrial-specific potassium channel TASK-1 regulates action potential duration (APD) and is differentially expressed in AF and left ventricular dysfunction, but the mechanisms controlling its expression are not well understood. ObjectiveThis study examines whether the transcription factor ETV1 regulates TASK-1 and contributes to atrial electrical remodelling. MethodsAtrial tissue from patients with and without AF was analysed to assess the relationship between ETV1 and TASK-1 (KCNK3) expression. In HL-1 cardiomyocyte-like cells and native fibroblasts, ETV1 activity was reduced using pharmacological inhibition or siRNA-mediated knockdown. TASK-1 expression, TASK-1 current, and APD at 90% repolarization were measured. Pacing experiments tested activity-dependent TASK-1 regulation. Direct transcriptional regulation was evaluated using ChIP-qPCR and ChIP-seq to detect ETV1 binding at the KCNK3 promoter. ResultsETV1 and TASK-1 levels were positively correlated in human atrial tissue. In HL-1 cells and fibroblasts, ETV1 inhibition or knockdown decreased TASK-1 expression and current and selectively prolonged APD90. Pacing-induced upregulation of TASK-1 was prevented by ETV1 inhibition, indicating a protective effect against pro-arrhythmic remodelling. ChIP-qPCR and ChIP-seq confirmed direct ETV1 binding to the KCNK3 promoter. ConclusionETV1 directly regulates TASK-1 expression and contributes to atrial electrical remodelling, identifying ETV1 as a potential upstream therapeutic target in AF. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/711402v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@3e5b25org.highwire.dtl.DTLVardef@1d1f909org.highwire.dtl.DTLVardef@34cf37org.highwire.dtl.DTLVardef@1105539_HPS_FORMAT_FIGEXP M_FIG C_FIG Translational perspectiveAtrial fibrillation is sustained by maladaptive electrical remodelling that remains insufficiently addressed by current rhythm-control therapies. Direct inhibition of individual ion channels has shown efficacy but is limited by phenotype dependence and proarrhythmic risk. The present data identify ETV1 as an upstream transcriptional regulator of the atrial-specific potassium channel TASK-1. Modulation of ETV1 reduced TASK-1 expression, prolonged atrial repolarisation, and prevented tachycardia-induced electrical remodelling in vitro. Targeting ETV1 may therefore represent a disease-modifying strategy that intervenes earlier in the remodelling cascade than conventional antiarrhythmic drugs. This approach could enable phenotype-guided therapy in atrial cardiomyopathy, particularly in patients with preserved ventricular function, and warrants validation in translational large-animal and clinical studies.

molecular biology↗