GSE134725 Identification and characterization of a transcribed distal enhancer involved in cardiac Kcnh2 regulation
Contributors : Malou van den Boogaard ; Jan H van Weerd ; Harmen J van de Werken ; Vincent M ChristoffelsSeries Type : OtherOrganism : Mus musculusThe human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying IKr, a current critical for the repolarization phase of the cardiac action potential. Mutations in KCNH2 that cause a reduction of the repolarizing current can result in cardiac arrhythmias associated with long QT syndrome. Here, we investigated the regulation of this critical cardiac gene and identified multiple active enhancers in the Kcnh2 locus. An enhancer ~85 kbp downstream of Kcnh2 physically contacted the promoters of two Kcnh2 isoforms in a cardiac-specific manner in vivo. Knockdown of a ncRNA controlled by this enhancer results in reduced expression of Kcnh2b and two neighboring mRNAs, Nos3 and Abcb8, in vitro. Genomic deletion of the enhancer, including the ncRNA transcription start site, from the mouse genome caused a modest downregulation of both Kcn2a and Kcn2b in the ventricles. These findings establish that the regulation of Kcnh2a and Kcnh2b is governed by a complex regulatory landscape that involves multiple partially redundantly acting enhancers.
The cardiac ventricular action potential depends on several voltage-gated ion channels, including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a speci...
ConclusionBoth mutations, KV7.1 A150T and L374H, led to loss of channel function. The degree of loss ‐of‐function may mirror the disease phenotype observed in the patients.This article is protected by copyright. All rights reserved
This report highlights a case of QT prolongation with torsades de pointes in a patient with baseline congenital long QT syndrome, believed to be precipitated by metabolic changes associated with the "ketogenic diet." PMID: 32063779 [PubMed]
Conclusion: Video-assisted CSD should be considered as a treatment option for patients with potentially dangerous arrhythmias that do not respond to conventional treatment, especially in recurrent ventricular tachycardia. PMID: 31588139 [PubMed - in process]
KCNH2 encodes the human ether- à-go-go-related gene (hERG) potassium channel, which passes the rapid delayed rectifier potassium current, IKr. Loss-of-function variants in KCNH2 cause long QT syndrome type 2 (LQTS2) which is associated with a markedly increased risk of cardiac arrhythmias. The majority of rare KCNH2 variants how ever are likely to be benign.
Publication date: 3 September 2019Source: Cell Reports, Volume 28, Issue 10Author(s): Malou van den Boogaard, Jan Hendrik van Weerd, Amira C. Bawazeer, Ingeborg B. Hooijkaas, Harmen J.G. van de Werken, Federico Tessadori, Wouter de Laat, Phil Barnett, Jeroen Bakkers, Vincent M. ChristoffelsSummaryThe human ether-a-go-go-related gene KCNH2 encodes the voltage-gated potassium channel underlying IKr, a current critical for the repolarization phase of the cardiac action potential. Mutations in KCNH2 that cause a reduction of the repolarizing current can result in cardiac arrhythmias associated with long-QT syndrome. Here, we i...
AbstractLong QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classicallytorsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnorma...
In conclusion, we identified a novel hERG channel activator HW-0168 that can be used for studying the physiological role of hERG in cardiac myocytes and may be beneficial for treating long QT syndrome.
This article summarizes the diseases that we have learned about, such as the long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The article examines the diagnosis, genetic screening of patients and their relatives, management, and referral to a specialist for further therapy. PMID: 31378327 [PubMed - in process]
This article summarizes the diseases that we have learned about, such as the long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The article examines the diagnosis, genetic screening of patients and their relatives, management, and referral to a specialist for further therapy.