Journal ArticleDOI
A novel mutation in KCNH2 yields loss-of-function of hERG potassium channel in long QT syndrome 2
Kai Gu,Duoduo Qian,Huiyuan Qin,Chang Cui,W C Hewith A Fernando,Daowu Wang,Juejin Wang,Kejiang Cao,Minglong Chen +8 more
Reads0
Chats0
TLDR
Wang et al. as discussed by the authors identified a novel KCNH2 mutation W410R in the patient with long QT syndrome 2 (LQT2), but the electrophysiological functions of this mutation remain unknown.Abstract:
Mutations in hERG (human ether-a-go-go-related gene) potassium channel are closely associated with long QT syndromes. By direct Sanger sequencing, we identified a novel KCNH2 mutation W410R in the patient with long QT syndrome 2 (LQT2). However, the electrophysiological functions of this mutation remain unknown. In comparison to hERGWT channels, hERGW410R channels have markedly decreased total and surface expressions. W410R mutation dramatically reduces hERG channel currents (IKr) and shifts its steady-state activation curve to depolarization. Moreover, hERGW410R channels make dominant-negative effects on hERGWT channels. Significantly, we find hERG channel blocker E-4031 could partially rescue the function of hERGW410R channels by increasing the membrane expression. By using in silico model, we reveal that hERGW410R channels obviously elongate the repolarization of human ventricular myocyte action potentials. Collectively, W410R mutation decreases the currents of hERG channel, because of diminished membrane expression of mutant channels, that subsequently leads to elongated repolarization of cardiomyocyte, which might induce the pathogenesis of LQT2. Furthermore, E-4031 could partially rescue the decreased activity of hERGW410R channels. Thus, our work identifies a novel loss-of-function mutation in KCNH2 gene, which might provide a rational basis for the management of LQT2.read more
Citations
More filters
Journal ArticleDOI
Predictive genomic tools in disease stratification and targeted prevention: a recent update in personalized therapy advancements
Journal ArticleDOI
Aborted Cardiac Arrest in LQT2 Related to Novel KCNH2 (hERG) Variant Identified in One Lithuanian Family.
Neringa Bileišienė,Jūratė Barysienė,Violeta Mikštienė,Eglė Preikšaitienė,Germanas Marinskis,Monika Keževičiūtė,Algirdas Utkus,Audrius Aidietis +7 more
TL;DR: A resuscitated 31-year-old male with the diagnosis of Long QT syndrome type 2 and his family were described in this article, where sequencing analysis of their genomic DNA was performed.
Journal ArticleDOI
Structural analysis of hERG channel blockers and the implications for drug design.
TL;DR: In this paper , the authors used computational modeling to study the implications of hERG mutations on hERG structure and trafficking, the interactions of HERG with hERG chaperone proteins and with membrane-soluble molecules, the mechanisms of drugs that inhibit hERG trafficking and drugs that rescue hERG mutants.
References
More filters
Journal ArticleDOI
A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel
TL;DR: The finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT, and that an additional subunit may be required for drug sensitivity.
Journal ArticleDOI
A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome
Mark E. Curran,Igor Splawski,Katherine W. Timothy,Vincent Gm,Eric D. Green,Keating Mt,Keating Mt +6 more
TL;DR: In this article, the authors investigated patients with long QT syndrome (LQT), an inherited disorder causing sudden death from a ventricular tachyarrythmia, torsade de pointes.
Journal ArticleDOI
Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation
TL;DR: A model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is developed and experiments for rate dependence of Ca2+ (including peak and decay) and intracellular sodium ([Na+]i) in undISEased human myocytes were quantitatively reproduced by the model.
Journal ArticleDOI
Prevalence of the Congenital Long-QT Syndrome
Peter J. Schwartz,Marco Stramba-Badiale,Lia Crotti,Matteo Pedrazzini,Alessandra Besana,Giuliano Bosi,Fulvio Gabbarini,Karine Goulene,Roberto Insolia,Savina Mannarino,Fabio Mosca,Luigi Nespoli,Alessandro Rimini,Enrico Rosati,Patrizia Salice,Carla Spazzolini +15 more
TL;DR: This study provides the first data-based estimate of the prevalence of LQTS among whites and advances the hypothesis that this prevalence might be close to 1:2000, thus allowing effective preventive measures.
Journal ArticleDOI
hERG K+ Channels: Structure, Function, and Clinical Significance
TL;DR: The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death.