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Genotype and Severity of Long QT Syndrome.

Sudden cardiac death is a significant problem in the United States, where the incidence is reported to be greater than 300 000 affected persons per year.[1] Although coronary heart disease is a major cause of death, other etiologies contribute to this problem. In cases in which no structural heart disease can be identified, arrhythmias resulting from such disorders as the long QT syndromes (LQTSs) are now commonly considered to be likely causes. The purposes of this article are to describe the current understanding of the phenotypic and molecular genetic aspects of LQTS and to correlate these features with disease severity.


Long QT syndromes are diagnosed by surface electrocardiograms, clinical presentation, and family history.[1-5] These disorders of repolarization are characterized by the electrocardiographic abnormalities of prolongation of the QT interval corrected for heart rate (QTc), relative bradycardia, T-wave abnormalities, and episodic ventricular tachyarrhythmias,[2] particularly torsade de pointes (Figure 1). The diagnosis usually relies on a QTc measurement of greater than 460 to 480 milliseconds using the formula3 QTc = QT/[square root] RR, with associated T-wave abnormalities. Long QT syndrome occurs either as an inherited disorder, sporadic disorder, or it may be acquired. In the latter case, acquired LQTS may be seen after the use of a variety of medications (eg, antiarrhythmic medications, antihistamines, psychotropic drugs, antifungal drugs, or macrolide antibiotics) or with electrolyte abnormalities, such as hypokalemia. The clinical presentation is similar in all forms of LQTS, however. Two inherited forms of LQTS with differing patterns of transmission have been described and include Romano-Ward syndrome (RWS)[5,6] and Jervell and Lange-Nielsen syndrome (JLNS).[7]

Romano-Ward syndrome is the most common inherited form of LQTS and is transmitted as an autosomal-dominant trait[1,2.5,6]; gene carriers are expected to be clinically affected (ie, they have evidence of LQTS) and have a 50% likelihood of transmitting the disease-causing gene to their offspring. However, low penetrance has been described, and therefore gene carriers may in fact have no clinical features of disease.[8] Individuals with RWS present with a prolonged QT interval on their electrocardiogram with the associated symptom complex of syncope, sudden death, and, in some patients, seizures.[9,10] Occasionally, other noncardiac abnormalities, such as diabetes mellitus,[11] asthma,[12] or syndactyly,[13] may also be associated with QT prolongation. Long QT syndrome may also be involved in some cases of sudden infant death syndrome.[14-16] However, no other organ system is usually associated.

Jervell and Lange-Nielsen syndrome is an uncommon inherited form of LQTS. Classically, this disease has been described as having apparent autosomal-recessive transmission.7 These patients have the identical clinical presentation as those with RWS, but also have associated sensorineural deafness.[7,17,18] Individuals with JLNS usually have longer QT intervals as compared to individuals with RWS and also have a more malignant course. Recently, this distinction has been blurred, as autosomal-recessive cases of RWS have been described.[19]


The first gene for autosomal-dominant LQTS was mapped by Keating et al[20,21] to chromosome 11p15.5 (LQT1), followed shortly thereafter with the realization that LQTS locus heterogeneity existed (ie, multiple genes cause LQTS).[22-25] This was confirmed when Jiang et al[26] mapped the LQT2 and LQT3 genes to chromosome 7q35-36 and to chromosome 3p21-24, respectively. Schott et al[27] mapped the fourth LQTS locus to chromosome 4q25-27 (LQT4), while a fifth gene (minK), located on chromosome 21q22,[28,29] was shown to be LQT5. More recently, a sixth gene, the minK-related peptide 1 (MiRP1), localized to 21q22 as well (Figure 2), was identified.[30] Several other families with autosomal-dominant LQTS are not linked to any known LQTS loci, indicating the existence of additional LQTS-causing genes.



Positional cloning[31] was used to identify the LQT1 gene on chromosome 11p15.5, the gene initially localized by Keating et al.[20,22] This gene was found to be a novel potassium channel gene, initially called KVLQT1 and later renamed KCNQ1. This potassium channel [Alpha]-subunit consists of 16 exons; spans approximately 400 kilobases (kb); and is widely expressed in human tissues, including heart, kidney, lung, inner ear, placenta, and pancreas, but not in skeletal muscle, liver, or brain. Eleven different mutations (deletion and missense mutations) were initially identified, establishing KVLQT1 (KCNQ1) as LQT1. To date, more than 100 families with mutations have been described, most with their own novel "private" mutations. However, there is at least 1 frequently mutated region (ie, hot spot) of this gene.[31,32] This gene is now believed to be the most commonly mutated gene in LQTS.[32,33]

Analysis of the predicted amino acid sequence of the encoded protein suggests that it encodes a potassium channel [Alpha]-subunit with a conserved potassium-selective, pore-signature sequence flanked by 6 membrane-spanning segments (Figure 2).[28,29,31] A putative voltage sensor is found in the fourth membrane-spanning domain (S4), and the selective pore loop is between the fifth and sixth membrane-spanning domains (S5, S6). Electrophysiologic characterization of the KVLQT1 (KCNQ1) protein in various heterologous systems confirmed this protein to be a voltage-gated potassium channel protein subunit, which requires a [Beta]-subunit to function properly.[28,29] This [3-subunit, which coassembles with KVLQT1 (KCNQ1), is called mink or KCNE1, and encodes a short protein with only 130 amino acids and only 1 transmembrane-spanning segment (Figure 2).[34] At the time of its initial identification, mink did not have any sequence or structural homologies to any other cloned channels, but it is now known to be part of a protein family.[30] When mink and KVLQT1 were coexpressed in either mammalian cell lines or Xenopus oocytes, a potassium current similar to the slowly activating potassium current ([I.sub.Ks]) in cardiac myocytes (Figure 3) was formed.[28,29] The physical interaction between KVLQT1 and mink was also confirmed by immunoprecipitation experiments.[28] A combination of normal and mutant KVLQT1 [Alpha]-subunits was found to form abnormal [I.sub.Ks] channels and, hence, LQTS-associated mutations of KVLQT1 (KCNQ1) are believed to act predominantly through a dominant-negative mechanism (the mutant form of KVLQT1 interferes with the function of the normal wild-type form through a "poison pill"-type mechanism) or a loss-of-function mechanism (only the mutant form loses activity).[35]

Since mutations in KVLQT1 were shown to cause LQTS (LQT1), mutations in minK were sought because mink plays an essential role in the development of [I.sub.Ks] (see "LQT5: minK").[36]



Both LQT2 and LQT3 were identified by the positional candidate gene approach. The candidate gene approach relies on a mechanistic hypothesis based on knowledge of the physiology of the disease of interest. Since LQTS is considered to be a disorder of abnormal repolarization, genes encoding ion channels or proteins modulating channel function were considered candidates for LQTS. After the initial localization of LQT2 to chromosome 7q35-36, candidate genes in this region, including ion channels, modifiers of ion channels, and genes encoding elements of the sympathetic nervous system, were analyzed. HERG (human ether-a-go-go-related gene), a cardiac potassium channel gene with 6 transmembrane segments (Figure 2) originally cloned from a brain complementary DNA library[37] and found to be expressed in neural crest-derived neurons,[38] microglia,[39] a wide variety of tumor cell lines,[40] and the heart,[41] was one of the genes evaluated. Curran et al[41] demonstrated linkage of HERG to the LQT2 locus on chromosome 7q35-36, and 6 LQTS-associated mutations were identified in HERG, including missense mutations, intragenic deletions, and a splicing mutation. Later, Schulze-Bahr et al[42] reported a single-base-pair deletion and a stop codon mutation in HERG, confirming this gene to be a common cause of LQTS when mutated. Currently, this gene is thought to be the second most common gene mutated in LQTS (second to KVLQT1), and mutations scattered throughout this entire gene have been seen. No hot spots have been recognized.

HERG consists of 16 exons and spans 55 kb of genomic Sequence.[41] The predicted topology of HERG is shown in Figure 2 and is similar to KVLQT1. Unlike KVLQT1, HERG has extensive intracellular amino and carboxyl termini, with a region in the carboxyl terminal domain having a sequence similarity to nucleotide binding domains.

Electrophysiologic and biophysical characterization of expressed HERG in Xenopus oocytes established that HERG encodes the rapidly activating delayed-rectifier potassium current [I.sup.Kr] (Figure 3).[43,44] Electrophysiologic studies of LQTS-associated mutations showed that they act through either a loss-of-function or a dominant-negative mechanism.[45] In addition, protein trafficking abnormalities have been shown to occur.[46,47] This channel has been shown to coassemble with [Beta]-subunits for normal function, similar to that seen in [I.sub.Ks]. McDonald et al[48] initially suggested that the complexing of HERG with mink is needed to regulate the [I.sub.Kr] potassium current. More recently, Abbott et al[30] identified MiRP1 as a [Beta]-subunit for HERG (see "LQT6: MiRP1").


The positional candidate gene approach was also used to establish that the gene responsible for chromosome 3-linked LQTS (LQT3) is the cardiac sodium channel gene SCN5A.[49,50] SCN5A is highly expressed in human myocardium, but not in skeletal muscle, liver, or uterus.[50,51] Recently, it was shown to be expressed in the brain.[52] This gene encodes [I.sub.Na], which is responsible for initiation of depolarization (Figure 3). It consists of 28 exons that span 80 kb and encodes a protein of 2016 amino acids with a putative structure that consists of 4 homologous domains (DI-DIV), each of which contains 6 membrane-spanning segments (S1-S6), similar to the structure of the potassium channel [Alpha]-subunits (Figure 2).[31-41] Linkage studies with LQT3 families and SCN5A initially demonstrated linkage to the LQT3 locus on chromosome 3p21-24.[51] In addition, 3 mutations, one 9-bp intragenic deletion ([K.sub.1505][P.sub.1506][Q.sub.1507]) and 2 missense mutations ([R.sub.1644][H and [N.sub.1325]S) were identified in 6 LQTS families (Figure 2). All 3 mutations were expressed in Xenopus oocytes, and all mutations generated a late phase of inactivation-resistant, mexiletine- and tetrodotoxin-sensitive, whole-cell currents through multiple mechanisms.[51,53-55] Two of the 3 mutations showed dispersed reopening after the initial transient, but the other mutation showed both dispersed reopening and long-lasting bursts.[55] These results suggested that SCN5A mutations act through a gain-of-function mechanism (the mutant channel functions normally, but with altered properties, such as delayed inactivation) and that the mechanism of chromosome 3-1inked LQTS is persistent non-inactivated sodium current in the plateau phase of the action potential. Later, An et al[56] showed that not all mutations in SCN5A are associated with persistent current. Furthermore, Wei et al[57] identified a C terminal SCN5A mutation, E1784K, which results in fast inactivation characterized by small, persistent current during long membrane depolarizations. These authors coexpressed the mutant with human sodium channel [[Beta].sub.1]-subunits, which did not affect the persistent current, even though shift in the voltage dependence of steady-state inactivation was seen. Neutralizing multiple negatively charged residues in the C terminus did not cause a more severe functional defect, suggesting that an allosteric effect, rather than a direct effect, in channel gating was responsible for channel dysfunction.

Another interesting finding was reported by Nagatomo et al[58] who found that [Delta]KPQ mutations have temperature-dependent activation and inactivation kinetics. At physiologic temperature, whole-cell patch-clamp studies in HEK293 cells found faster inactivation and activation kinetics. In addition, faster decay was notable at voltages negative to -20 mV, suggesting reduced voltage dependence of fast inactivation.

Furthermore, mutations in SCN5A were identified by our laboratory in patients with a significantly different clinical phenotype.[59] Brugada syndrome, characterized by ST elevation in leads [V.sub.1] to [V.sub.3], with or without right bundle branch block and ventricular fibrillation,[60] was found to occur from SCN5A mutations. At least 1 of these mutations (R1623Q) results in more rapid recovery from inactivation of the mutant channels or loss of function. The specific mechanism causing the differences between LQTS and Brugada syndrome is not known. Interestingly, a very close mutation (T1623) results in classic LQTS.[61]

LQT5: minK

minK (IsK or KCNE1) was initially localized to chromosome 21 (21q22.1) and found to consist of 3 exons that span approximately 40 kb. It encodes a short protein consisting of 130 amino acids and has only 1 transmembrane-spanning segment with small extracellular and intercellular regions (Figure 2).[34,62] When expressed in Xenopus oocytes, it produces potassium current that closely resembles the slowly activating delayed-rectifier potassium current [1.sub.Ks] in cardiac cells.[34,60] Initially, the minK clone could only be expressed in Xenopus oocytes and not in mammalian cell lines. However, with the cloning of KVLQT1 and coexpression of KVLQT1 and minK in both mammalian cell lines and Xenopus oocytes, it was recognized that minK alone cannot form a functional channel, but induces the [I.sub.Ks] current by interacting with endogenous KVLQT1 protein in Xenopus oocytes and mammalian cells (Figure 3). McDonald et al[48] showed that minK complexes with HERG regulate the [I.sub.Kr] potassium current as well. The importance of minK to the function of the [I.sub.Ks] was shown when Splawski et al[36] identified mutations in 2 families with LQTS. In both cases, missense mutations (S74L, D76N) were identified that reduced [I.sub.Ks] by shifting the voltage dependence of activation and accelerating channel deactivation. Recently, minK was found to be a cofactor in the expression of both [I.sub.Ks] and [I.sub.Kr], and mutations in minK were shown to affect both channels. Trafficking abnormalities occur as well.[63] The functional consequences of these mutations included delayed cardiac repolarization and, hence, an increased risk of arrhythmias.


MiRP1, the minK-related peptide 1, or KCNE2, is a novel potassium channel gene recently cloned and characterized by Abbott and colleagues.[30] MiRP1 is a 123-amino-acid channel protein with a single predicted transmembrane segment similar to that described for minK.[34] Chromosomal localization studies mapped this KCNE2 gene to chromosome 21q22.1 (Figure 2), within 79 kb of KCNE1 (minK) and arrayed in opposite orientation.[30] The open reading frames of these 2 genes share 34% identity, and both are contained in a single exon, suggesting that they are related through gene duplication and divergent evolution. This small integral membrane subunit protein assembles with HERG (LQT2) to alter its function, enabling full development of the [I.sub.Kr] current (Figure 3). Three missense mutations associated with LQTS and ventricular fibrillation were identified in KCNE2 by Abbott et al,[30] and biophysical analysis demonstrated that these mutants form channels that open slowly and close rapidly, thus diminishing potassium currents. In one case (Q9E), the mutation led to acquired (drug-induced) torsade de pointes and ventricular fibrillation. None of the mutations caused classic LQTS, however.

Therefore, like minK, this channel protein acts as a [Beta]-subunit, but by itself, leads to ventricular arrhythmia risk when mutated. These similar channel proteins (ie, minK and MiRP1) suggest that a family of channels exist that regulate ion channel [Alpha]-subunits. The specific role of this subunit remains unclear and is currently being hotly debated.


Neyroud et al[64] reported the first molecular abnormality in patients with JLNS when they reported on 2 families in which 3 children were affected by JLNS and in whom a novel homozygous deletion-insertion mutation of KVLQT1 in 3 patients was found, which resulted in premature termination at the C-terminal end of the KVLQT1 channel. This finding was confirmed when Splawski et al[65] identified a homozygous insertion of a single nucleotide, which caused a frame shift in the coding sequence after the second putative transmembrane domain (S2) of KVLQT1 in a family with JLNS. Together, these data strongly suggested that at least 1 form of JLNS is caused by homozygous mutations in KVLQT1. This finding has been confirmed by others.[35,65-68]

It is interesting that, in general, heterozygous mutations in KVLQT1 cause RWS (LQTS only), while homozygous mutations in KVLQT1 cause JLNS (LQTS and deafness). The likely explanation is as follows: although heterozygous KVLQT1 mutations act by a dominant-negative mechanism, some functional KVLQT1 potassium channels till exist in the stria vascularis of the inner ear Therefore, congenital deafness is averted in patients with heterozygous KVLQT1 mutations. For patients with homozygous KVLQT1 mutations, no functional KVLQT1 potassium channels can be formed. It has been shown by in situ hybridization that KVLQT1 is expressed in the inner ear,[64] suggesting that homozygous KVLQT1 mutations can cause the dysfunction of potassium secretion in the inner ear and lead to deafness. However, it should be noted that incomplete penetrance exists, and not all heterozygous or homozygous mutations follow this rule.[8,19]

Schulze-Bahr et al[69] showed that mutations in minK result in JLNS syndrome as well. Hence, abnormal [I.sub.Ks] current, whether it occurs due to homozygous mutations in KVLQT1 or minK result in LQTS and deafness.


Zareba et al[70] recently showed that the mutated gene may result in a specific phenotype and predict outcome. For instance, they showed that mutations in LQT1 and LQT2 result in early symptoms (ie, syncope), but the risk of sudden death was relatively low for any event. In contrast, mutations in LQT3 resulted in a paucity of symptoms, but when symptoms occurred, they were associated with a high likelihood of sudden death. Mutations in LQT1 and LQT2 appeared to be associated with stress-induced symptoms, including response to auditory triggers, while LQT3 appeared to be associated with sleep-associated symptoms. In addition, bradycardia and exercise-induced QT shortening have been seen in LQT3 patients.[71] Coupled with the findings of Moss et al[72] that differences in the electrocardiographic patterns could be identified based on the gene mutated (Figure 4), it could be suggested that understanding the underlying cause of LQTS in any individual could be used to improve survival.



Currently, the standard therapeutic approach in LQTS is the initiation of [Beta]-blockers at the time of diagnosis.[2] Recently, Moss et al[73] demonstrated significant reduction in cardiac events using [Beta]-blockers. However, syncope, aborted cardiac arrest, and sudden death do continue to occur In cases in which [Beta]-blockers cannot be used, as in patients with asthma, other medications have been tried, such as mexiletine. When medical therapy fails, left sympathectomy or implantation of an automatic cardioverter defibrillator have been utilized.

Recently, genetic-based therapy has been described. Schwartz et al[71] showed that sodium channel blocking agents (ie, mexiletine) shorten the QTc in patients with LQT3, and Compton et al[74] and Shimizu et al[75] demonstrated that exogenous potassium supplementation or potassium channel openers, respectively, may be useful in patients with potassium channel defects. Tan and colleagues[76] attempted long-term potassium therapy with associated potassium-sparing agents and found that they were unable to keep the serum potassium level above 4 mmol/L, owing to renal potassium homeostasis. This finding suggests that potassium therapy may not be useful in the long term. In addition, no definitive evidence that these approaches (ie, sodium channel blockers, exogenous potassium, or potassium channel openers) improve survival has been published.


Shimizu and Antzelevitch,[77,78] using an arterially perfused canine left ventricular wedge preparation, developed pharmacologically induced animal models of LQT1, LQT2, and LQT3. Using chromanol 293B, a specific [I.sub.Ks] blocker, the authors produced a model that mimics LQT1.[77] In this model, [I.sub.Ks] deficiency alone was not enough to induce torsade de pointes, but addition of [Beta]-adrenergic influence (ie, isoproterenol) predisposed the myocardium to torsade by increasing transmural dispersion of repolarization. Addition of [Beta]-blocker or mexiletine reduced the ability to induce torsade, suggesting these medications might improve patient outcomes.

Models for LQT2 and LQT3 were created by using d-sotalol (LQT2) or ATX-II (LQT3) in this wedge preparation.[78] Both of these drugs preferentially prolong M-cell action potential duration, with ATX-II also causing a sharp rise in transmural dispersion. Mexiletine therapy abbreviated the QT interval prolongation in both models and reduced dispersion as well. Spontaneous torsade de pointes was suppressed, and the vulnerable window during which TdP-induction occurs was also reduced in both models. These models support the current understanding of the different subtypes of LQTS and provide an explanation for potential therapies.


Long QT syndromes are genetically and clinically heterogeneous. The affected gene in any patient can lead to a wide spectrum of clinical outcomes, depending on its specific mutation. These mutations, however, remain difficult to identify. Once the genetic mutation is known, gene-specific therapy may be an option in the future.


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Accepted for publication August 30, 2000.

From the Departments of Pediatrics (Cardiology) (Drs Twbin and Li), Cardiovascular Sciences (DRs Towbin and Wang), and Molecular and Human Genetics (Dr Towbin), Texas Children's Hospital and Baylor College of Medicine, Hoston, Tex.

Presented at the Ninth Annual William Beaumont Hospital DNA Technology Symposium, DNA Technology in the Clinical Laboratory, Royal Oak, Mich, April 13-15, 2000.

Reprints: Jeffrey A. Towbin, MD, Department of Pediatrics (Cardiology), Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030.
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Author:Towbin, Jeffrey A.; Wang, Zhiqing; Li, Hua
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Jan 1, 2001
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