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      Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

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          Abstract

          Aims

          Long-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS.

          Methods and results

          We produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a I Kr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K + currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations).

          Conclusions

          These findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.

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          Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

          Peter J. Schwartz, Silvia G Priori, Carla Spazzolini … (2001)
          The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
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            Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism.

            Craig T. January, Melissa L. Anderson, Qiuming Gong … (2006)
            The KCNH2 or human ether-a-go-go related gene (hERG) encodes the Kv11.1 alpha-subunit of the rapidly activating delayed rectifier K+ current (IKr) in the heart. Type 2 congenital long-QT syndrome (LQT2) results from KCNH2 mutations that cause loss of Kv11.1 channel function. Several mechanisms have been identified, including disruption of Kv11.1 channel synthesis (class 1), protein trafficking (class 2), gating (class 3), or permeation (class 4). For a few class 2 LQT2-Kv11.1 channels, it is possible to increase surface membrane expression of Kv11.1 current (IKv11.1). We tested the hypotheses that (1) most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels, and (2) their trafficking-deficient phenotype can be corrected. Wild-type (WT)-Kv11.1 channels and 34 missense LQT2-Kv11.1 channels were expressed in HEK293 cells. With Western blot analyses, 28 LQT2-Kv11.1 channels had a trafficking-deficient (class 2) phenotype. For the majority of these mutations, the class 2 phenotype could be corrected when cells were incubated for 24 hours at reduced temperature (27 degrees C) or in the drugs E4031 or thapsigargin. Four of the 6 LQT2-Kv11.1 channels that had a wild-type-like trafficking phenotype did not cause loss of Kv11.1 function, which suggests that these channels are uncommon sequence variants. This is the first study to identify a dominant mechanism, class 2, for the loss of Kv11.1 channel function in LQT2 and to report that the class 2 phenotype for many of these mutant channels can be corrected. This suggests that if therapeutic strategies to correct protein trafficking abnormalities can be developed, it may offer clinical benefits for LQT2 patients.
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              The QT syndromes: long and short.

              Hiroshi Morita, Jiashin Wu, Douglas P Zipes (2008)
              This Seminar presents the most recent information about the congenital long and short QT syndromes, emphasising the varied genotype-phenotype association in the ten different long QT syndromes and the five different short QT syndromes. Although uncommon, these syndromes serve as a Rosetta stone for the understanding of inherited ion-channel disorders leading to life-threatening cardiac arrhythmias. Ionic abnormal changes mainly affecting K(+), Na(+), or Ca(2+) currents, which either prolong or shorten ventricular repolarisation, can create a substrate of electrophysiological heterogeneity that predisposes to the development of ventricular tachyarrhythmias and sudden death. The understanding of the genetic basis of the syndromes is hoped to lead to genetic therapy that can restore repolarisation. Presently, symptomatic individuals are generally best treated with an implantable cardioverter defibrillator. Clinicians should be aware of these syndromes and realise that drugs, ischaemia, exercise, and emotions can precipitate sudden death in susceptible individuals.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Eur Heart J
                Journal ID (iso-abbrev): Eur. Heart J
                Journal ID (publisher-id): eurheartj
                Journal ID (hwp): ehj
                Title: European Heart Journal
                Publisher: Oxford University Press
                ISSN (Print): 0195-668X
                ISSN (Electronic): 1522-9645
                Publication date (Print): 21 April 2014
                Publication date (Electronic): 6 March 2013
                Publication date PMC-release: 6 March 2013
                Volume: 35
                Issue: 16 , Focus Issue on Heart Failure
                Pages: 1078-1087
                Affiliations
                [1 ]Wolfson Centre for Stem Cells, Tissue Engineering and Modelling (STEM), University of Nottingham , Nottingham NG7 2RD, UK
                [2 ]Department of Medicine and Radiology, Stanford University School of Medicine , Stanford, CA 94305-5111, USA
                [3 ]Clinical Chemistry, Queen's Medical Centre , NottinghamNG7 2UH, UK
                [4 ]Max-Planck-Institute for the Physics of Complex Systems , Nöthnitzer Straße 38, Dresden 01187, Germany
                [5 ]Department of Cardiovascular Medicine, Queen's Medical Centre , NottinghamNG7 2UH, UK
                [6 ]School of Biosciences, Cardiff University , CardiffCF11 9BX, UK
                [7 ]School of Biology, University of Nottingham , Nottingham NG7 2RD, UK
                Author notes
                [* ]Corresponding author. Tel: +44 0 115 82 31236, Fax: +44 0 115 82 31230. Email: chris.denning@ 123456nottingham.ac.uk
                Article
                Publisher ID: eht067
                DOI: 10.1093/eurheartj/eht067
                PMC ID: 3992427
                PubMed ID: 23470493
                SO-VID: fc895054-360f-49fb-9bb5-59c528143975
                Copyright © © The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial use, distribution, and reproduction in any medium, provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 3 October 2012
                Date revision received : 27 November 2012
                Date accepted : 7 February 2013
                Page count
                Pages: 10
                Categories
                Subject: Basic Science
                Series title: Editor's choice

                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: ips cells,long-qt syndrome,arrhythmia,electrophysiology,gene therapy
                Data availability:
                ScienceOpen disciplines: Cardiovascular Medicine
                Keywords: ips cells, long-qt syndrome, arrhythmia, electrophysiology, gene therapy

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