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KCNH2 Mutations and Cardiac Arrhythmias

KCNH2 Mutations and Cardiac Arrhythmias

Over the past 20 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, “ion channelopathies”, in which mutations in genes encode functional units of ion channels and their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital short QT syndrome, long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders. More importantly, these studies play an important role in the development of potentially more effective pharmacological agents and even curative gene therapy.

KCNH2 channel

The KCNH2 gene, or human ether-a-go-go related gene (hERG), codes for a potassium voltage-gated ion channel. The current through the channel is termed the rapid component of the cardiac delayed rectifier (IKr). The KCNH2 gene is located on chromosome 7 and has 15 exons. The Kv channels, which include Shaker, Kv1.2, KvAP and hERG, are formed by coassembly of four identical α-subunits, each containing six α-helical transmembrane domains, S1–S6 (Figure 1). Each subunit comprises two functionally distinct modules, one that senses transmembrane potential (S1–S4) and one that forms the K+-selective pore (S5–S6).

Figure 1. Diagram of a single hERG subunit

KCNH2 mutations cause cardiac arrhythmia

LQTS is defined by prolongation of the QT interval measured by a body surface electrocardiogram (ECG) and a greatly increased risk of ventricular fibrillation. The QT interval is the time required for ventricular repolarization during a single cardiac cycle (Figure 2). Delayed repolarization increases the risk of torsade de pointes (TdP), a unique cardiac arrhythmia characterized by an ECG trace that resembles a waxing and waning sine wave. TdP can either revert to a normal sinus rhythm or degenerate into lethal ventricular fibrillation. LQTS affects an estimated 1 in 5,000–10,000 people worldwide and is caused most often by dominant mutations in KCNH2 or KCNQ1, the α-subunit for the channel that conducts the slow delayed rectifier K+ current, IKs. Less commonly, mutations in accessory β-subunits that coassemble with KCNH2 or KCNQ1 α-subunits cause LQTS. Mutations in any of the α- or β-subunits reduce outward K+ conductance, slow the rate of action-potential repolarization and result in electrical instability that can generate TdP.

Figure 2. Reduced hERG current delays ventricular repolarization and can induce arrhythmia

There are more than 100 reported mutations in the KCNH2 gene related to congenital LQTS. The functional consequence of most KCNH2 mutations is a disruption of the folding of subunits and of trafficking of the channel to the cell surface membrane. Mutated and misfolded KCNH2 subunits are usually retained in the endoplasmic reticulum in the core-glycosylated form and are rapidly degraded by the ubiquitin-proteasome pathway. Mutations can also alter KCNH2 gating or cause dominant negative suppression when mutant and wild-type subunits coassemble. The finding that both loss- and gain-of-function mutations in KCNH2 can cause lethal arrhythmia emphasizes that normal electrical activity of the heart requires a finely balanced expression of ion channels.


LQT2 is caused by loss-of-function mutations in the KCNH2-encoded human-ether-a-go-go-related gene K+-channel 1 (hERG1 or Kv11.1) and is responsible for an estimated 25–30% of all LQTS cases. The assem¬bly of four full-length hERG1a α subunits—or a combi¬nation of hERG1a and the shorter, alternatively spliced hERG1b isoform—form the tetrameric Kv11.1 channel that conducts IKr. KCNH2 mutations have elucidated multiple mechanisms responsible for IKr loss-of-function in LQT2, including nonsense-mediated decay, defective Kv11.1 protein synthesis, impaired Kv11.1 protein trafficking, and kinetic alterations in channel gating and K+ selectivity or K+ permeation. Defective Kv11.1 protein trafficking—which encompasses defective protein folding, retention in the endoplasmic reticulum, and disrupted trafficking to the Golgi apparatus or to the cell surface—represents the dominant molecular mechanism in LQT2 and is thought to underlie the functional consequences of an estimated 80–90% of KCNH2 missense mutations. However, the function of many trafficking-deficient Kv11.1 channels can be rescued by high-affinity hERG-blocking drugs, such as fexofenadine or aminoglycoside antibiotics.

Diagnosis and therapy in inherited arrhythmogenic disorders

Currently, the use of induced pluripotent stem cell (iPSC) technology to study inherited arrhythmogenic disorders has become a new paradigm, because it can provide direct evidence linking genetic mutations to cardiac arrhythmias in humans. The iPSC technology is to reprogram somatic cells into pluripotent stem cells via transduction of a key set of transcriptional factors. Human iPSCs can differentiate to functional cardiac myocytes (CMs), and similar to human ESCs these human iPSCs have a capacity of differentiating into nodal-, atrial-, and ventricular-like cells, each with specific AP characteristics; both iPSC- and ESC-derived CMs exhibit typical responsiveness to BAS. Therefore, the possibility of creating patient- and disease-specific human iPSC-derived CMs aimed at individualized diagnostic and pharmacological testing has become a reality. Up to now, iPSC-derived CMs have been assessed in a limited number of patients with ion channelopathies.

In iPSC-derived CMs produced from a patient with A614V missense in KCNH2, there was a prolongation of AP duration, which could be ascribed to significant reduction of IKr. These iPSC-derived CMs with KCNH2A614 also exhibited marked arrhythmogenicity characterized by EADs and EAD-mediated TA. K+-channel blockers could aggravate, whereas Ca2+-channel blockers, IK(ATP)-channel openers, and late Na+-channel blockers could ameliorate the disease phenotype. In another patient with KCNH2G1681A, iPSC-derived CMs72 also showed prolonged AP duration. Exposure to E4031 (an IKr blocker) provoked EADs. Furthermore, isoprenaline facilitated EADs; this latter effect may be reversed by β-blockers. In an asymptomatic patient with KCNH2R176W whose sister and father had died suddenly at an early age, iPSC-derived CMs with such a mutation showed prolonged AP duration and dramatically reduced IKr density. These iPSC-derived CMs with KCNH2R176W are sensitive to potentially arrhythmogenic drugs such as sotalol, and exhibited a pronounced inverse correlation between the beating rate and repolarization time. Hence, iPSC-derived CMs may be used to provide a direct way for identifying asymptomatic patients at risk of proarrhythmia.

Future directions

Technology with the ability to generate human iPSCs has become a new paradigm for pathophysiological study of patient- and disease-specific cells and for screening of new drugs, and clinical application of gene therapy. However, because this technology is relatively new, the validity and reproducibility of the findings need to be carefully verified. Human iPSC-derived CMs are usually immature, more akin to fetal CMs, as yet to recapitulate all the characteristics of adult CMs. In addition, better purification of human iPSC-derived CMs is needed. It is anticipated that continued efforts and collaboration between basic science and clinical researchers are required to overcome difficulties concerning the use of iPSC technology in the diagnosis and management of arrhythmic disorders in clinical practice.

Gene Cell Lines Premade Virus Particles cDNAs
  Stable cell lines Overexpression Knockdown Adenovirus Lentivirus ORF Full-Length
CSC-SC007949 CSC-DC007949 AD08406Z LV15950L
CSC-SC007999 CSC-DC007999 AD08456Z LV16042L


  1. Sanguinetti&Amp M C, Tristani-Firouzi M. Review article hERG potassium channels and cardiac arrhythmia. Nature, 2006(7083):463-469.
  2. Altman R B. KCNH2 pharmacogenomics summary. Pharmacogenetics & Genomics, 2010, 20(12):775.
  3. Pi-Yin H, et al. Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies. Application of Clinical Genetics, 2013, 6(default):1-13.
  4. Giudicessi J R, Ackerman M J. Potassium-channel mutations and cardiac arrhythmias—diagnosis and therapy. Nature Reviews Cardiology, 2012, 9(6):319-32.

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