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Modeling long QT syndrome using gene-edited pigs

ABSTRACT: Modeling long QT syndrome using gene-edited pigs

PROVIDER: PRJNA1216026 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32133615_1.fastq.gz	Fastqsanger.gz
	SRR32133615_2.fastq.gz	Fastqsanger.gz
	SRR32133616_1.fastq.gz	Fastqsanger.gz
	SRR32133616_2.fastq.gz	Fastqsanger.gz
	SRR32133617_1.fastq.gz	Fastqsanger.gz

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Modeling long QT syndrome using gene-edited pigs

Project description:To date, KCNH2 mutations identified in LQT2 patients have been heavily studied by heterologous expression systems, allowing for pathogenicity evaluation of a certain hERG mutation by overexpressing mutant channels. However, they fall short in mimicking the full spectrum of electrophysiological changes and ion channel remodeling that occur in cardiomyocytes under physiological conditions in the context of LQT. Due to the marked differences in the lifespan, size, anatomy and physiology from humans, current zebrafish and rodent models cannot fully mimic the abnormal QT interval diseases 2. For instance, rodents exhibit an extremely higher heart rate and a much shorter action potential duration (APD) compared to humans. IKr is the predominant repolarizing current in human ventricles while inhibition of IKr in rodents has no significant effect on ventricular repolarization, making it infeasible to study LQT2 by genetic mouse model 3. Hence, there is a crucial need to construct an animal model capable of mimicking human inherited arrhythmia conditions. To address the above scientific question, we chose to create a miniature pig model. Given many physiological similarities with humans, and breeding and genome editing advantages (when compared to non-human primates), To explore the mechanism underlying mutation of KCNH2 caused LQT, we compared the transcriptomes of KCNH2-mut pigs and WT controls

2025-02-03 | GSE288082 | GEO

Modeling long QT syndrome type 2 on-a-chip via in-depth assessment of isogenic gene-edited 3D cardiac tissues.

Project description:Long QT syndrome (LQTS) is a cardiovascular disease characterized by QT interval prolongation that can lead to sudden cardiac death. Many mutations with heterogeneous mechanisms have been identified in KCNH2, the gene that encodes for hERG (Kv11.1), which lead to onset of LQTS type 2 (LQTS2). In this work, we developed a LQTS2-diseased tissue-on-a-chip model, using 3D coculture of isogenic stem cell-derived cardiomyocytes (CMs) and cardiac fibroblasts (CFs) within an organotypic microfluidic chip technology. Primarily, we created a hiPSC line with R531W mutation in KCNH2 using CRISPR-Cas9 gene-editing technique and characterized the resultant differentiated CMs and CFs. A deficiency in hERG trafficking was identified in KCNH2-edited hiPSC-CMs, revealing a possible mechanism of R531W mutation in LQTS2 pathophysiology. Following creation of a 3D LQTS2 tissue-on-a-chip, the tissues were extensively characterized, through analysis of calcium handling and response to β-agonist. Furthermore, attempted phenotypic rescue via pharmacological intervention of LQTS2 on a chip was investigated.

| S-EPMC9757749 | biostudies-literature

Induced pluripotent stem cell modeling of patients and drugs at risk for QT prolongation

Project description:Induced pluripotent stem cell modeling of patients and drugs at risk for QT prolongation

| PRJNA671350 | ENA

T he proteostasis interactomes of trafficking - deficient K V 11.1 variants associated with Long QT Syndrome and pharmacological chaperone rescue

Project description:The voltage gated potassium ion channel KV11.1 plays a critical role in cardiac repolarization. Genetic variants that render Kv11.1 dysfunctional cause Long QT Syndrome (LQTS), which is associated with fatal arrhythmias. Approximately 90% of LQTS-associated variants cause intracellular protein transport (trafficking) dysfunction, which can be rescued by pharmacological chaperones like E-4031. Protein folding and trafficking decisions are regulated by chaperones, protein quality control factors, and trafficking machinery comprising the cellular proteostasis network. Here, we test whether trafficking dysfunction is associated with alterations in the proteostasis network of pathogenic Kv11.1 variants, and whether pharmacological chaperones can normalize the proteostasis network of responsive variants.

2024-08-10 | PXD050914 | Pride

PGRN-RIKEN:Genome-Wide Association Study of Drug-Induced Long-QT Syndrome

Project description:PGRN-RIKEN:Genome-Wide Association Study of Drug-Induced Long-QT Syndrome

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Long QT syndrome.

Project description: Not available

| S-EPMC3153516 | biostudies-literature

Enhancers implicate new genes in QT interval below GWAS detection threshold

Project description:Our goal is to identify high-confidence candidate genes associated with sub-threshold QT interval loci. We predicted enhancer-promoter targets using two different methods.

2014-10-10 | GSE53567 | GEO

Peribacillus frigoritolerans QT-140 TE12474

Project description:Peribacillus frigoritolerans QT-140 TE12474 genome sequencing

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QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome.

Project description:BackgroundIncreased variability of QT interval (QTV) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long QT syndrome (LQTS), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and QTV.Methods and resultsTwenty-four-hour Holter monitor tracings from 78 genotyped congenital LQTS patients (52 females; 51 LQT1, 23 LQT2, 2 LQT5, 2 JLN, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer-assisted annotation of RR and QT intervals. Several models of RR-QT relationship were tested in all patients. A model assuming exponential decrease of past RR interval contributions to QT duration with 60-second time constant provided the best data fit. This model was used to calculate QTc and residual "intrinsic" QTV, which cannot be explained by heart rate change. The intrinsic QTV was higher in patients with long QTc (r=0.68; P<10(-4)), and in LQT2 than in LQT1/5 patients (5.65±1.28 vs 4.46±0.82; P<0.0002). Both QTc and intrinsic QTV were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively).ConclusionsIn LQTS patients, QT interval adaptation to heart rate changes occurs with time constant ≈60 seconds, similar to results reported in control subjects. Intrinsic QTV correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of LQTS.

| S-EPMC4845278 | biostudies-literature

Enhancers implicate new genes in QT interval below GWAS detection threshold

Project description:Our goal is to identify high-confidence candidate genes associated with sub-threshold QT interval loci. We predicted enhancer-promoter targets using two different methods. 1) We used the correlation in activity between enhancers and transcribed genes across 59 human cell lines and tissues to identify significantly correlated enhancer-promoter pairs that represent potential regulatory interactions. 2) We used chromosome conformation capture followed by high-throughput sequencing (4C-seq) to probe physical enhancer-promoter interactions.

2014-10-10 | E-GEOD-53567 | biostudies-arrayexpress

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