KCNH2 Mutations Research Articles

Arrhythmia Phenotype During Fetal Life Suggests Long-QT Syndrome Genotype

Background— Fetal arrhythmias characteristic of long QT syndrome (LQTS) include torsades de pointes (TdP) and/or 2° atrioventricular block, but sinus bradycardia, defined as fetal heart rate <3% for gestational age, is most common. We hypothesized that prenatal rhythm phenotype might predict LQTS genotype and facilitate improved risk stratification and management. Method and Results— Records of subjects exhibiting fetal LQTS arrhythmias were reviewed. Fetal echocardiograms, neonatal ECG, and genetic testing were evaluated. We studied 43 subjects exhibiting fetal LQTS arrhythmias: TdP±2° atrioventricular block (group 1, n=7), isolated 2° atrioventricular block (group 2, n=4), and sinus bradycardia (group 3, n=32). Mutations in known LQTS genes were found in 95% of subjects tested. SCN5A mutations occurred in 71% of group 1, whereas 91% of subjects with KCNQ1 mutations were in group 3. Small numbers of subjects with KCNH2 mutations (n=4) were scattered in all 3 groups. Age at presentation did not differ among groups, and most subjects (n=42) were live-born with gestational ages of 37.5±2.8 weeks (mean±SD). However, those with TdP were typically delivered earlier. Prenatal treatment in group 1 terminated (n=2) or improved (n=4) TdP. The neonatal heart rate–corrected QT interval (mean±SE) of group 1 (664.7±24.9) was longer than neonatal heart rate–corrected QT interval in both group 2 (491.2±27.6; P =0.004) and group 3 (483.1±13.7; P <0.001). Despite medical and pacemaker therapy, postnatal cardiac arrest (n=4) or sudden death (n=1) was common among subjects with fetal/neonatal TdP. Conclusions— Rhythm phenotypes of fetal LQTS have genotype-suggestive features that, along with heart rate–corrected QT interval duration, may risk stratify perinatal management.

Cardiac Channelopathies Associated with Infantile Fatal Ventricular Arrhythmias: From the Cradle to the Bench

Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear. Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1-5, KCNJ2, SCN5A, GJA5, and CALM1 by using denaturing high-performance liquid chromatography and direct sequencing. Whole-cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A, and 1 mutation (p.G628D) in KCNH2. N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin-sensitive persistent late Na(+) currents. By contrast, SCN5A-T290fsX53 was nonfunctional. KCNH2-G628D exhibited loss of channel function. Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation.

Mutant hERG channel traffic jam. Focus on “Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum”

ION CHANNELS ARE MACROMOLECULAR pore-forming structures that regulate the selective distribution of ions across the cell membrane or between intracellular compartments. They are fundamental in several physiological processes including cell volume regulation, neurotransmission, and muscle contraction. Therefore, it is not surprising that disruption of ion channel function by genetic mutation can be associated with cardiovascular disorders. KCNH2, also known as the human ether-a-go-go related gene (hERG), encodes the pore-forming subunit of a delayed rectifier voltage-dependent K channel (9). These channels are expressed in numerous cell types, but are most notable for their role in the heart. Normal hERG K channel activity is important for maintaining cardiac electrical activity. The gating properties of hERG K channels makes their contribution ideal for prolonging the duration of the plateau phase (slow activation and rapid inactivation) and for initiating the terminal repolarization phase (rapid recovery from inactivation and slow deactivation) of the action potential. Controlling action potential duration is critical for ensuring sufficient Ca 2 entry to enable cardiac contraction, while the delayed repolarization phase provides some protection against premature contractions (9). Loss-of-function (LOF) mutations can attenuate hERG K channel activity, thus increasing the propensity for the development of life-threatening arrhythmias. For example, LOF mutations in KCNH2 can cause chromosome 7-linked long QT (type 2; LQT2) syndrome, a disorder characterized by abnormal cardiac electrical activity, due to prolongation of the QT interval (2). Although this LOF can be attributed to decreased expression, dominant-negative (DN) effects, or changes in

Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum

KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K(+) current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4-5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential.

Mechanistic Basis for Type 2 Long QT Syndrome Caused by KCNH2 Mutations that Disrupt Conserved Arginine Residues in the Voltage Sensor

KCNH2 encodes the Kv11.1 channel, which conducts the rapidly activating delayed rectifier K+ current (I Kr) in the heart. KCNH2 mutations cause type 2 long QT syndrome (LQT2), which increases the risk for life-threatening ventricular arrhythmias. LQT2 mutations are predicted to prolong the cardiac action potential (AP) by reducing I Kr during repolarization. Kv11.1 contains several conserved basic amino acids in the fourth transmembrane segment (S4) of the voltage sensor that are important for normal channel trafficking and gating. This study sought to determine the mechanism(s) by which LQT2 mutations at conserved arginine residues in S4 (R531Q, R531W or R534L) alter Kv11.1 function. Western blot analyses of HEK293 cells transiently expressing R531Q, R531W or R534L suggested that only R534L inhibited Kv11.1 trafficking. Voltage-clamping experiments showed that R531Q or R531W dramatically altered Kv11.1 current (I Kv11.1) activation, inactivation, recovery from inactivation and deactivation. Coexpression of wild type (to mimic the patients' genotypes) mostly corrected the changes in I Kv11.1 activation and inactivation, but deactivation kinetics were still faster. Computational simulations using a human ventricular AP model showed that accelerating deactivation rates was sufficient to prolong the AP, but these effects were minimal compared to simply reducing I Kr. These are the first data to demonstrate that coexpressing wild type can correct activation and inactivation dysfunction caused by mutations at a critical voltage-sensing residue in Kv11.1. We conclude that some Kv11.1 mutations might accelerate deactivation to cause LQT2 but that the ventricular AP duration is much more sensitive to mutations that decrease I Kr. This likely explains why most LQT2 mutations are nonsense or trafficking-deficient.

Personalized medicine for long QT syndrome: Restoration of ion channel function with RNA interference technology

With a prevalence of 1/2500, long QT Syndrome (LQTS) is one of the leading causes of sudden cardiac death in young and otherwise healthy individuals. LQTS is a proarrhythmic disorder hallmarked by prolongation of cardiac repolarization due to underlying ion channelopathies. This translates to the typical electrocardiographic (ECG) findings of prolonged QT interval, notched or biphasic T waves, and T wave alternans, and puts individuals at high risk of developing ventricular tachyarrhythmias and sudden cardiac death. To date, there are 13 subtypes of LQTS classified according to the 13 identified genetic defects, all encoding subunits of cardiac ion channels (Kþ , Naþ , Ca2þ) or ion channel regulatory proteins. Current treatment options for LQTS including beta-blockers, left cardiac sympathetic denervation, and implantable cardioverter-defibrillators are largely palliative [1]. Each of these existing modalities is associated with limitations such as adverse effects related to drug and surgical therapies and the limited lifespan of implantable devices. In the age of molecular genetics, a molecular diagnosis of the underlying ion channel defect not only establishes the disease state but paves the way for personalized medicine. Recently, Lu et al. adopted the use of RNA interference technology to target and rescue the channelopathy phenotype observed in LQTS type 2 due to KCNH2 mutation [2]. RNA interference therapy is based on the concept derived from the natural cellular mechanism where sequence-specific gene silencing can be achieved by creation of double-stranded RNA [3]. A synthetic effector small

Non-Coding Data in KCNH2 mRNA Control Translation and Trafficking Efficiencies

The KCNH2 gene encodes a K+ channel important to normal cardiac electrophysiology. Its significance is underscored by its link to both hereditary (locus LQT2) and acquired Long-QT cardiac arrhythmias. Over 400 deleterious mutations have been reported throughout the KCNH2 length. Why the channel is so susceptible to missense mutations is unclear. More than 50% of LQT2 mutations result in defective assembly and trafficking. There is evidence that even wild type channels are processed inefficiently. It has also been reported that the channel protein may reach the surface via atypical pathways. Most attention has logically focused on the protein for these processes.Much less is known about mRNA-dependent factors in channel processing. We analyzed the coding mRNA sequence of KCNH2. It has 66% GC content and 60 potential hair-pin loop segments. We re-synthesized the cDNA to achieve 50% GC-content and reduce the number of potential hair-pin loops while maintaining identical amino acid coding. Cellular expression of the codon-modified cDNA (CM-KCNH2) produced ionic currents comparable to native cDNA. Channel protein was expressed in a dramatically different pattern. Whereas the native protein (NT-KCNH2) is usually more abundant (immature form) in ER/Golgi compartments than on the surface, CM-KCNH2 showed a preponderance of the mature form, indicating channels at the surface. Immunofluorescence analysis confirmed this localization. From these results we hypothesize that KCNH2 translation efficiency, determined by RNA sequence-specific elements independent of coding, affect downstream protein assembly and/or trafficking_an unusual occurrence. As a corollary to this, we postulate a synergy between the inherently inefficient biosynthesis of KCNH2 and LQT2 mutations that contribute to the pathogenesis of hereditary LQT2. Further investigation of mechanisms underlying mRNA-dependent processing of KCNH2 channels may lead us to reconsider approaches to hereditary and acquired arrhythmia syndromes.

A case of long QT syndrome with triple gene abnormalities: Digenic mutations in KCNH2 and SCN5A and gene variant in KCNE1

molecular genetic studies have identi-fied 13 different forms of congenital LQTS caused bymutations in the genes of potassium, sodium, and calciumchannels or membrane adaptors. Recent studies also showedthat common candidate gene variants are associated with QTinterval duration in the general population.

Abstract 9821: Fetal Rhythm Phenotype Predicts LQTS Mutation: Risk Stratification of Perinatal Long QT Syndrome

Introduction: Torsade de pointe (TdP) and/or 2° atrioventricular block (2° AVB) are signature rhythms for perinatal LQTS known for their high morbidity and mortality. We hypothesized that the clinical profile of patients with complex fetal arrhythmias might be mutation specific. Methods: Perinatal records of subjects with LQTS exhibiting complex fetal arrhythmia were reviewed. Fetal echocardiograms, neonatal ECG and genetic testing were evaluated. Results: We studied 11 LQTS subjects exhibiting complex fetal arrhythmias. Mutation in a known LQTS gene was identified in 9: SCN5A (5), KCNH2 (2) and KCNQ1 (2). Most mutations were de novo including 4 SCN5A-1623Q. TdP occurred in 8 cases (7 prenatal, mean gestational age=30.5 weeks). Most fetuses with TdP also had 2° AVB, but 3 cases had 2° AVB alone. TdP exhibited 2 patterns: fast (&gt;270 bpm) and incessant or slow (&lt;250 bpm) and intermittent. All cases with SCN5A mutation had fast-incessant TdP, while cases with KCNH2 mutations had slow-intermittent TdP. Cases with KCNQ1 mutations had 2° AVB. Fetuses with TdP were delivered earlier (33.6 weeks) than those with 2° AVB (38.5 weeks). Neonatal QTc intervals were 652 ± 42 (in utero TdP) and 507 ± 43, p=0.01 (in utero 2° AVB). Prenatal treatment was administered in 6 cases without maternal complications; 4 fetuses improved and TdP ceased in 2. Despite medical and pacemaker therapy, cardiac arrest (n=6) resulting in sudden death (n=2) were common. Conclusion: Complex rhythm phenotypes of fetal LQTS have mutation specific features that may allow risk stratification in these high risk patients.

Mission possible: RNA interference rescues the hERG current

The congenital long QT syndrome (LQTS) is an inherited disease that causes cardiac arrhythmias and sudden cardiac death in the absence of evident structural heart defects. It is mainly attributed to genetic mutations that affect the function of ion channels that regulate the action potential waveform. LQTS is characterized by an abnormal prolongation of cardiac repolarization, leading to an increased QT interval, notched or biphasic T waves, and T-wave alternans. Affected patients are at a higher risk for developing arrhythmias, including polymorphic ventricular tachycardia, torsades de pointes, and ventricular fibrillation. The estimated prevalence of LQTS (based on electrocardiographic-guided identification of disease-causing mutations among whites) is approximately 1:2500 in apparently healthy live births. LQTS was initially described in the Jervell and Lange-Nielsen syndrome, where QT prolongation and deafness were present. A few years later, an autosomal dominant form of LQTS, in the absence of deafness, was reported. During the last decade, 13 LQTS variants have been described. Mutations in KCNQ1, KCNH2, and SCN5A genes account for approximately 90% of the positivegenotype cases of LQTS and underlie LQTS1, LQTS2, and LQTS3. Those genes encode Kv7.1, Kv11.1, and Nav1.5, respectively. Genetic analyses have identified more than 200 LQTS2causing mutations in KCNH2. Missense mutations leading to single amino acid substitutions in hERG (human ethera-gogo-related gene) protein—the alpha subunit of the rapid delayed rectifier current (IKr)—are the predominant abnormality. At the functional level, these mutations result in a decreased IKr. 11 It has been shown that LQTS2 mutations reduce IKr through a variety of mechanisms including aberrant hERG protein folding, trafficking, or ion-channel gating. Although not all identified mutations have been investigated, the majority of the mutations produce failure of the hERG subunits to exit the endoplasmic

Mutation location matters in long QT syndrome type 2 (but behavior matters more)

The KCNH2 (hERG) gene is responsible for the major (a) protein subunit of the rapidly activating delayed rectifier K + current (IKr) channel, which provides an essential repolarizing current in cardiac myocytes. Patients with mutations in KCNH2 have long QT syndrome type 2 and, depending on the tremendous variability in expression resulting from the complex variations in the rest of their genome, may present as phenotypically normal or may have QT prolongation with or without symptoms of syncope or cardiac arrest from torsades de pointes ventricular tachycardia. In order to form a functional IKr channel, the protein subunits must undergo glycosylation in the endoplasmic reticulum, coassemble into tetramers, and traffic to the cell membrane. Intracellular “quality-control” machinery can recognize abnormally folded/glycosylated proteins and prevent trafficking to the cell membrane. For the most part, mutations in the nonpore part of KCNH2 cause failure of mutant subunits to coassemble and traffic to the membrane, leaving heterozygous individuals with half the usual number of IKr channels (haplotype insufficiency). 1 In contrast, patients with muta

A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome

Long QT syndrome (LQTS) is characterized by prolonged ventricular repolarization and variable clinical course with arrhythmia-related syncope and sudden death. Mutations in the nonpore region of the LQTS-associated KCNH2 gene (also known as hERG) are mostly associated with coassembly or trafficking abnormalities, resulting in haplotype insufficiency and milder clinical phenotypes compared with mutations in the pore domain. To investigate the effect of a nonpore mutation on the channel current, which was identified from an LQTS family with severe clinical phenotypes. Two members of a Japanese family with LQTS were searched for mutations in KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and KCNJ2 genes by using automated DNA sequencing. We characterized the electrophysiological properties and glycosylation pattern of the mutant channels by using patch clamp recording and Western blot analysis. In the LQTS patient with torsades de pointes and cardiopulmonary arrest, we identified the novel T473P mutation in the transmembrane nonpore region of KCNH2. The proband's father carried the same mutation and showed prolonged corrected QT interval and frequent torsades de pointes in the presence of hypokalemia following the administration of garenoxacin. Patch clamp analysis in heterologous cells showed that hERG T473P channels generated no current and exhibited a dominant negative effect when coexpressed with wild-type protein. Only incompletely glycosylated hERG T473P channels were observed by using Western blot analysis, suggesting impaired trafficking. These results demonstrated that a trafficking-deficient mutation in the transmembrane nonpore region of KCNH2 causes a dominant negative effect and a severe clinical course in affected patients.

Angeborenes Langes QT-Syndrom

Inherited long QT syndrome (LQTS) is characterized by a prolonged ventricular repolarization (QTc interval) and symptoms (syncope, sudden cardiac arrest) due to polymorphic ventricular arrhythmias. As of today, 13 different cardiac ion channel genes have been associated with congenital LQTS. The most common ones are due to KCNQ1 (LQT-1), KCNH2 (LQT-2), and SCN5A (LQT-3) gene mutations and account for up to 75% of cases. Typical clinical findings are an increased QT interval on the surface electrocardiogram, specifically altered T wave morphologies, polymorphic ventricular arrhythmias, or an indicative family history. Recently, in the HRS/EHRA expert consensus statement, comprehensive genetic testing of major LQTS genes was recommended for index patients for whom there is a strong clinical suspicion of LQTS. Overall, antiadrenergic therapy, in particular β-receptor blockers, has been the mainstay of therapy and has significantly reduced cardiac events. For high-risk patients, an implantable cardioverter defibrillator (ICD) is recommended. Importantly, lifestyle modification and avoidance of arrhythmia triggers are additional important approaches.

Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing

BackgroundClassic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. Methods and ResultsOne hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. ConclusionsIncidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis.

Complexities of 5'splice site definition: Implications in clinical analyses

In higher eukaryotes, the 5' splice site (5'ss) is initially recognized through an RNA-RNA interaction by U1 small nuclear ribonucleoprotein (U1 snRNP). This event represents one of the key steps in initial spliceosomal assembly and many disease-associated mutations in humans often disrupt this process. Beside base pair complementarity, 5'ss recognition can also be modified by additional factors such as RNA secondary structures or the specific binding of other nuclear proteins. In this work, we have focused on investigating a few examples of changes detected within the 5'ss in patients, that would not be immediately considered "disease causing mutations". We show that the splicing outcome of very similar mutations can be very different due to variations in trans-acting factor(s) interactions and specific context influences. Using several NF1 donor sites and SELEX approaches as experimental models, we have examined the binding properties of particular sequence motifs such as GGGU found in donor sites, and how the sequence context can change their interaction with hnRNPs such as H/F and A1/A2. Our results clearly show that even minor differences in local nucleotide context can differentially affect the binding ability of these factors to the GGGU core. Finally, using a previously identified mutation in KCNH2 that resulted in intron retention we show how very similar 5'ss mutations found in patients can have a very different splicing outcome due to the neighbouring sequence context, thus highlighting the general need to approach splicing problems with suitable experimental approaches.

Is medroxyprogesterone safe in women with long QT syndrome?

G Twenty-two percent of women in the United States use depot medroxyprogesterone acetate (MPA) at some stage in their life for contraception. It is highly effective, can be elf-administered, and has high adherence rates. The World ealth Organization lists it as a first-line option for young omen, particularly those wishing to avoid the adverse ffects of estrogens, such as breast-feeding mothers, smokrs, those who are overweight, and those with atrial fibrilation, pulmonary hypertension, valvular heart disease, and ypertension in pregnancy. Thus, when a case report apears suggesting a possible link between MPA and QT rolongation with cardiac arrest, the evidence needs to be eviewed carefully; the impact of withdrawal or even cauion with MPA could be massive. Giudicessi et al report a woman with a frame shift mutation in KCNH2 (long QT type 2) who in her midtwenties had 2 episodes of ventricular arrhythmia with a prolonged QT interval while taking MPA over a period of 16 months overall. Once MPA was discontinued, no further events occurred over the next 6 years, including 2 further uneventful pregnancies and postpartum periods. Women are more prone than men to the QT-prolonging effects of drugs. Most such drugs exert their effect on the otassium channel IKr, the channel that is defective in long T syndrome type 2. Nevertheless, the case comes as a urprise since it seems beyond doubt both from clinical and n vitro studies that while estrogen prolongs the QT interval, rogesterone (and testosterone) shortens it. The QT-proonging effects of some drugs, for example, ibutilide, are itigated by progesterone. During pregnancy in long QT type 2, the risk of cardiac events is reduced. This is believed to be due to the protective (QT-shortening) effect of endogenous progesterone. During the postpartum period, the protective effect of endogenous progesterone disappears and there is an immediate high risk of cardiac events. In a transgenic rabbit model of long QT type 2, progesterone reduces the incidence of arrhythmia.

Peripartum Cardiomyopathy Presenting with Syncope due to Torsades de Pointes: a Case of Long QT Syndrome with a Novel KCNH2 Mutation

Peripartum cardiomyopathy (PPCM) is a cardiomyopathy of unknown cause that occurs in the peripartum period. We report a case of PPCM presenting with syncope 1 month after an uncomplicated delivery. Electrocardiography showed Torsades de pointes (TdP) and QT interval prolongation. Echocardiography showed left ventricular systolic dysfunction and endomyocardial biopsy showed myocyte degeneration and fibrosis. Administration of magnesium sulfate and temporary pacing eliminated recurrent TdP. Genetic analyses revealed that recurrent TdP occurred via electrolyte disturbance and cardiac failure due to PPCM on the basis of a novel mutation in KCNH2, a gene responsible for inherited type 2 long QT syndrome.

Benign Premature Ventricular Complexes from the Right Ventricular Outflow Tract Triggered Polymorphic Ventricular Tachycardia in a Latent Type 2 LQTS Patient

A 57-year-old woman showed frequent premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT), and some of the PVCs triggered polymorphic ventricular tachycardia (PVT). Structural heart diseases were ruled out by conventional cardiac examinations. Radiofrequency catheter ablation was successful in eliminating the PVCs and subsequent PVT. However, epinephrine infusion unmasked her prolonged QT interval, and a genetic analysis revealed a KCNH2 mutation (R694H) as the cause of latent type-2 long QT syndrome (LQTS). This case suggests that latent LQTS may work as an arrhythmogenic substrate of PVT triggered by a benign form of RVOT-PVCs in patients with a structurally normal heart.

Enhanced impact of SCN5A mutation associated with long QT syndrome in fetal splice isoform

Congenital long QT syndrome (LQTS) is an inherited syndrome characterized by prolongation of the QT interval on the electrocardiogram and an increased susceptibility to life-threatening ventricular arrhythmias. Mutations in the SCN5A gene, which encodes the α-subunit of the cardiac Na+ channel, represent the third most common cause of LQTS, after mutations in potassium channel genes KCNQ1 and KCNH2. Moreover, mutations in SCN5A have been linked to other types of inherited channelopathies, including the Brugada syndrome, progressive familial heart block type 1, sick sinus syndrome type 1, idiopathic ventricular fibrillation, familiar atrial standstill, dilated cardiomyopathy type 1E, and sudden infant death syndrome (SIDS).

Abstract 17271: An Alternatively Spliced Kcnh2 Variant Restores Cardiac Repolarization in a Model of Long QT Syndrome: Implications for Phenotypic Variation in Human Long QT Syndrome

Introduction: Mutations in KCNH2 ( HERG1 , LQT-2) are a common cause of Long QT Syndrome (LQTS). Despite sharing the same mutation, affected family members often display marked differences in disease severity, including risk of sudden cardiac death. The genetic basis of this phenotypic variation is not known. We previously validated a zebrafish model of human LQT-2. Here, we use a repolarization-deficient zebrafish mutant ( breakdance , bre ) to probe the molecular basis of phenotypic variation. Methods: Bre is due to a recessive kchn2 mutation (I59S) within the cytoplasmic N-terminal domain. 5’-RACE and qPCR were used to clone and quantify novel N-terminal variants from zebrafish and human heart. Biophysical properties of zebrafish and human variants were characterized using voltage- and patch-clamp techniques. In vivo functional effects were determined by over-expressing the variants in knch2-null zebrafish embryos, and assaying for ability to restore ventricular repolarization by characterizing phenotypes of the embryonic heart at 48 hour-post-fertilization. Results: We identified a novel, alternatively spliced N-terminal variant, kcnh2 1c , with in-frame deletion of Exon 2-6. The 1c variant constitutes ~40% of the kcnh2 transcript, and is expressed 4X greater in atrium than ventricle. The 1c variant deletes the disease-causing mutation, I59S. Activation of kcnh2 1c channels is similar to WT, but deactivation is accelerated. In vivo , kcnh2 1c functions similar to WT, and is able to partially restore ventricular repolarization in knch2-null zebrafish. We identified 2 novel N-terminal variants in human heart that are also differentially expressed between the atrium and ventricle. Biophysical function of the human variants is similar to zebrafish 1c. Conclusion: Kcnh2 1c modulates cardiac repolarization in the bre mutant by excising the disease-causing mutation. Approximately 30% of LQT-2 mutations localize to the N-terminus, and are subject to alternative splicing. By excising N-terminal mutations human 1c variants may modulate repolarization and influence phenotypic expression in LQTS.