The Long QT Syndrome Family of Cardiac Ion Channelopathies: a Huge Review

The Long QT syndrome family of cardiac ion channelopathies: A HuGE review

(Expanded Web Version)

Stephen M. Modell, MD, MS1, and Michael H. Lehmann, MD2

From the 1Department of Health Management and Policy, University of Michigan School of Public Health;

2Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical System.

Corresponding Author:

Stephen M. Modell, MD, MS

University of Michigan

School of Public Health

M-4157, OCBPH, SPH-II

109 S. Observatory

Ann Arbor, MI 48109-2029

E-mail:

Print version submitted for publication July 27, 2005.

Accepted for publication December 16, 2005.

DOI: 10.1097/01.gim.0000204468.85308.86

ABSTRACT

Long QT syndrome (LQTS) refers to a group of ”channelopathies” – disorders that affect cardiac ion channels. The “family” concept of syndromes has been applied to the multiple LQTS genotypes, LQT1-8, which exhibit converging mechanisms leading to QT prolongation and slowed ventricular repolarization. The 470+ allelic mutations induce loss-of-function in the passage of mainly K+ ions, and gain-of-function in the passage of Na+ ions through their respective ion channels. Resultant early after depolarizations can lead to a polymorphic form of ventricular tachycardia known as torsade de pointes, resulting in syncope, sudden cardiac death, or near-death (i.e., cardiac arrest aborted either spontaneously or with external defibrillation). LQTS may be either congenital or acquired. The genetic epidemiology of both forms can vary with sub-population depending on the allele, but as a whole, LQTS appears in every corner of the globe. Many polymorphisms, such as HERG P448R and A915V in Asians, and SCN5A S1102Y in African-Americans, show racial-ethnic specificity. At least 9 genetic polymorphisms may enhance susceptibility to drug-induced arrhythmia (an “acquired” form of LQTS). Studies have generally demonstrated greater QT prolongation and more severe outcomes among adult females. Gene-gene interactions, e.g., between SCN5A Q1077del mutations and the SCN5A H558R polymorphism, have been shown to seriously reduce ion channel current. While phenotypic ascertainment remains a mainstay in the clinical setting, SSCP and DHPLC-aided DNA sequencing are a standard part of mutational investigation, and direct sequencing on a limited basis is now commercially available for patient diagnosis. Genet Med 2006:8(3):143-155.

Key Words: Long QT syndrome, ion channelopathies, torsade de pointes, epidemiology, review

GENES AND CORRESPONDING ELECTROPHYSIOLOGY

The congenital (also called ”idiopathic”) form of long QT syndrome (LQTS) is mainly caused by mutations in genes that code for protein subunits of cardiac ion channels, principally those responsible for the IKs (slow) and IKr (rapid) delayed rectifier potassium currents. The third most common variant results from a genetic mutation affecting cardiac sodium channels. The pace of LQTS gene discovery has accelerated since 1991 when the first genetic locus was identified.1 As of May 2005, 8 major genotypes, LQT1-8, 471 different mutations, and 124 polymorphisms were described in the European Society of Cardiology Working Group on Arrhythmias (WGA) LQTS gene database.2 Among the various LQTS genotypes, the most common feature predisposing to arrhythmia is prolongation of the ventricular action potential duration during cardiac repolarization, measured as the QT interval on the electrocardiogram (Fig. 1),3 which can lead to early after-depolarizations and life-threatening torsade de pointes (TdP)(Fig. 2).4 This converging mechanism has led some to ascribe the “family” concept to the various LQTS genotypes,5 though considerable heterogeneity exists. Table 1 depicts the range of genes composing the idiopathic “long QT syndromes” and their corresponding electrophysiology (Refs. 6-26).

Cellular electrophysiology

The ventricular action potential proceeds through five phases (cardiac action potential; Fig. 3).5 The initial upstroke (phase 0 - depolarization) occurs through the opening and closing of Na+ channels. The repolarization process begins with the rapid transient outflow of K+ ions (phase 1 – Ito current). This is followed by the flow of outward current through 2 delayed rectifier K+ channels (IKs, IKr) and of inward current through Ca2+ channels, constituting phase 2 or the plateau phase of repolarization. Increasing conductance of the rapid delayed rectifier (IKr) and inward rectifier (IK1) currents completes repolarization (phase 3). Phase 4 represents a return of the action potential to baseline.27 LQTS mutations act primarily on the IKs, IKr, and INa currents to prolong the cardiac action potential. The prolongation is registered by an increase in the heart-rate corrected QT interval, or QTc, on electrocardiographic tracings.3,28 Multiple studies have shown that prolongation of the action potential can lead to early afterdepolarizations (EADs) via an increase in L-type calcium current (ICa,L). EADs, through repetitive triggering and reentry circuits, are considered the most likely mechanisms for initiation and maintenance of TdP.6

Specific LQTS genotypes

The LQT1 gene (also known as KCNQ1 and KvLQT1) spans 400 kb and encodes voltage-gated potassium channel alpha subunits. A tetramer of 4 KCNQ1 alpha subunits co-assembles with the minK gene product (beta regulatory subunit) to form the IKs slowly deactivating delayed rectifier potassium channel.27 At least 179 KCNQ1, mostly missense, mutations have been reported.2 KCNQ1 mutations have been identified in the intracellular (N-terminal and C-terminal), transmembrane, and pore domains of the encoding gene sequence, with a few in the extracellular domain. For potassium channel mutations in general, mixed alpha subunit tetramers (wild-type plus mutated units) exhibit abnormal protein function, producing a dominant-negative effect on ion channel current.

By itself, the KCNQ1 encoded protein subunit typically induces a rapidly activating, slowly deactivating K+ outward current (IKs). However in the presence of minK, KCNQ1 channel activation is slowed down considerably. The net effect of LQT1 mutations is a decreased outward K+ current during the plateau phase of the cardiac action potential, i.e., a loss-of-function of the ion channel. The channel remains open longer, ventricular repolarization is delayed, and the QT interval is lengthened.27

The gene for LQT2 (also known as the KCNH2 and human ether-a-go-go--related or HERG gene) spans 55kb and also encodes potassium channel alpha subunits. Tetramers of these subunits form the IKr rapidly activating, rapidly deactivating delayed rectifier potassium channel, which associates with the minK-related peptide 1 (MiRP1) gene product.27 At least 198 distinct HERG mutations have been identified.2 HERG mutations are spread in roughly equal proportion throughout the N-terminal, membrane-spanning, pore region, and C-terminal domains. The majority of HERG pore region defects are missense mutations, while non-pore defects demonstrate a variety of missense, nonsense, and frameshift mutations.2,29

The literature on HERG abnormalities describes a variety of structural ion channel defects, as well as intracellular “trafficking” abnormalities - deficiencies resulting from subunits that are retained in the endoplasmic reticulum, never reaching the myocardial cell membrane.30,31 The first type of abnormality, mutant subunits having dominant-negative effects, can result in a > 50% reduction in channel function.27 Trafficking abnormalities, which also occur in LQT3,32 LQT5,33 and LQT7,34 can result in a 50% reduction in the number of functional channels (haploinsufficiency) due to missing protein subunits.29

In terms of electrophysiology, HERG mutations cause potassium ion channels to deactivate (close) much faster, blunting the normal rise in current (IKr) that results from rapid recovery from channel inactivation / slow deactivation. The IKr current during the plateau phase is reduced and ventricular repolarization delayed, leading to QT interval prolongation.27

The LQT3 gene, SCN5A, spans 80kb. At least 56 LQTS SCN5A mutations have been identified.2 The SCN5A alpha subunit, comprised of 4 sequential domains that fold end-to-end into a torus-like shape, can form a fully functional channel; beta subunits have a modifying influence. Normal or wild-type sodium channels open briefly during phase 0 of the cardiac action potential to allow influx of Na+ ions, thus depolarizing the cell, then inactivate quickly, leaving a small, residual inward current during the plateau phase. LQT3 mutations lead to the reopening of sodium channels (i.e., gain-of-function) during this time period, thereby enhancing the inward plateau current and prolonging repolarization.35

The gene responsible for LQT4, 220 kb in length, encodes the ankyrin-B (ANKB or ANK2) protein.36,37 This “adaptor” protein anchors ion transporters to specialized domains within the cell membrane, rather than itself transporting ions as happens with the gene products for the other long QT genotypes. The 5 reported AnkB mutations interfere with anchoring of Na,K-ATPase and the Na/Ca exchanger, resulting in Na+ build-up and a compensatory increase in intracellular Ca2+ stores.38 The latter can lead to after-depolarizations and fatal arrhythmias. A distinguishing feature is that QTc, though greater than average in groups tested, is inconsistently prolonged.23,38

The relatively small minK gene, mutations in which cause LQT5, is 40 kb in length. The encoded KCNE1 protein contains a single transmembrane spanning domain with small intra- and extracellular components. The product of the minK gene forms the beta subunit of the LQT1 assembly regulating the IKs potassium channel current. Evidence exists that it may also serve as a modulating factor for IKr channel expression.33 The name “minK” is derived from the now substantiated contention that the gene encodes the “mimimal” size potassium channel subunit.

The LQT6 gene encoding MiRP1, or minK-related protein 1, is located 70 kb from minK on the same chromosome.39 The two genes bear many similarities, suggesting a common evolutionary origin, possibly from a duplication event. Neither produces a current by itself. The MiRP1 gene product KCNE2 co-assembles as the beta subunit with HERG alpha subunits to regulate IKr potassium currents. Its structure is similar to that of minK’s. Mutations in MiRP1 are largely of the missense variety. LQT6 mutations generally lead to only modest QT prolongation.

The LQT7 genotype has been mapped to the inward rectifying potassium channel gene KCNJ2 on chromosome 17. KCNJ2 encodes the potassium channel protein Kir2.1. Kir2.1 plays an important role in the generation of inward repolarizing (IK1) currents during the terminal stages (phase 3) of the cardiac action potential.40 It also anchors the diastolic resting potential prior to depolarization.41 Kir subunits are believed to form tetramers in a fashion similar to KCNQ1 and HERG alpha protein subunits. More than 24 mutations affecting Kir2.1 residues have been documented.2,42 Families of mutations variously affect PIP2 (membrane-associated phospholipid) binding, pore loop function, and protein trafficking.34,42 Patients generally exhibit relatively modest QTc prolongation, with case series reporting rare degeneration into TdP and its sequellae.25 Owing to these features plus the characteristic T-U wave pattern, which may lead to misinterpreted “QT” prolongation, Zhang et al. have questioned the inclusion of KCNJ2 mutations in the LQTS family,24 though the designation is already somewhat established. More malignant, life-threatening mutations (R67W and C101R) have also been observed.43

The most recent addition, LQT8, has been mapped to the voltage-dependent calcium channel gene CACNA1C on chromosome 12. The expressed exon 8 and 8A protein product influence voltage-dependent Ca2+ current inactivation. CACNA1C mutations cause nearly complete loss of L-type Cav1.2 channel inactivation.20,26 The effect is to prolong the inward (depolarizing) Ca2+ current during the plateau phase (phase 2), with consequent slowing of repolarization (gain-of-function effect). Marked QT interval prolongation (as high as 730 ms) and fatal arrhythmias (often in the first 3 years) are characteristic. All individuals tested so far have had de novo mutations. Multisystemic features of LQT7 and LQT8 will be described in the Disease section.

The literature makes a fundamental distinction between the above LQTS genes and those factors responsible for QT variation in the general population. Various studies have postulated major genetic and environmental effects, as well as non-Mendelian multifactorial effects.44,45 Twin and population-based studies cast a wide net for heritability estimates of genetic factors explaining QT interval variation in the freestanding population – between 25 and 60%.44,46-49 A twin and a population-based study using Framingham Heart Study cohorts have suggested LQT1, 3, and 4 genes as possible quantitative trait loci in non-LQTS study participants.46,48 While there likely exists some role for LQT (or other) genes in determining QT variability in the general population, more work is needed to spell out this relationship.

GENE VARIANTS

Patterns in LQTS mutations

We conducted a MedSearch of the LQTS literature from major regions of each continent for the period 1975-2004 (Tables 2 and 3), and reviewed the mutation and polymorphism-related citations on the WGA and international Human Genome Organisation (HUGO) web sites (See Internet sites at end, and Tables 4 and 5). The mutations Medline search focused on articles including at least one human subject (i.e., case studies, case series, or larger); the polymorphisms search contained both human and nonhuman studies. International LQTS Registry-related (e.g., Italy and the U.S.), Brugada (see below) and other associated syndrome article searches were conducted separately. Tables 4 and 5 exclude mutations not referenced in the last 9 years, having incomplete tabular data, or representing nonfunctional intronic variants. Overall genotypic data appear separately.

The expanse of human subject-related articles demonstrates the presence of LQTS in virtually every corner of the globe. Several locales depict unique pockets of activity. France and Mexico have contributed to the LQT4 and LQT7 literature due to the presence of large families with rare mutations in each of these countries.36,37,40,52

Mutational site is may affect severity of the LQTS phenotype. In a subset of the International Long QT Syndrome Registry, patients and kin with LQT2 pore mutations appeaed to be at a higher risk for cardiac events than individuals with non-pore mutations.29 On the other hand, certain non-pore HERG mutations can give rise to a malignant phenotype.53 Though some studies have failed to demonstrate a consistent difference in phenotypic severity between pore vs. non-pore mutational sites in

LQT1, 54,55 a recent 5-center, 95 patient study in Japan indicated QTc may be prolonged to a greater extent in pore vs. pre-pore mutations.56 Investigators in the multicenter study also noted greater risk for patients with transmembrane compared to C-terminal mutations (55% vs. 21% frequency of cardiac events, p = 0.002). Two studies describing KCNQ1 mutations in Table 4 tend to support the finding of the multicenter Japanese study: a study of the mildly presenting C-terminal G589D mutation present in 30% of Finnish LQTS cases,57 and an investigation of 16 KCNQ1 mutations (15 transmembrane / 1 C-terminal) in 20 families by French investigators.58 However, a mutational screening survey in the U.S. of 541 unrelated, consecutive LQTS patients performed by Tester et al. failed to corroborate the above LQT1 and 2 relationships.59 Additional research is needed to resolve the disparate findings.

Cases and families bearing the same mutation may be separated by considerable distance, e.g., the HERG A614V missense mutation detected in Japanese families and multiple unrelated families of European descent,60 and the HERG S818L missense mutation detected in unrelated families from Belgium and Ireland.61 In many instances these recurrent genetic events are considered sporadic.62 However, alternative explanations exist. Tranebjaerg et al., who identified a JLNS R518X mutation on 2 different haplotypes in Norwegian families of Swedish and Scottish ancestry, note the difficulty of resolving whether the same mutation observed in the different groups is due to recurrent mutational events or a founder effect.63 Four alleles studied in the Finnish population – KCNQ1 G589D and IVS7-2A->G (KCNQ1-FinA and B, respectively), and HERG L552S and R176W (HERG-FinA and B, respectively) – represent founder mutations enriched by the historic isolation of that country.57,64