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PubMed2004

Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers.

CONTEXT: Data on the efficacy of beta-blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. OBJECTIVE: To describe and assess outcome in a large systematically genotyped population of beta-blocker-treated LQTS patients. DESIGN, SETTING, AND PATIENTS: Consecutive LQTS-genotyped patients (n = 335) in Italy treated with beta-blockers for an average of 5 years. MAIN OUTCOME MEASURES: Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received beta-blocker therapy according to genotype. RESULTS: Cardiac events among patients receiving beta-blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P =.001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from beta-blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P =.01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). CONCLUSION: Among patients with genetic LQTS treated with beta-blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.

Adrenergic beta-Antagonists↗
PubMed2005

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

CONTEXT: In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis. OBJECTIVE: To perform genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations. DESIGN, PATIENTS, AND SETTING: We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population. MAIN OUTCOME MEASURES: Development of a novel approach to LQTS genotyping. RESULTS: We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts. CONCLUSIONS: We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.

Algorithms↗
PubMed1996

Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome.

Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, predisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and characterized an LQT family consisting of 48 individuals. DNA was screened with 150 microsatellite polymorphic markers encompassing approximately 70% of the genome. We found evidence for linkage of the LQT phenotype to chromosome 7(q35-36). Marker D7S636 yielded a maximum lod score of 6.93 at a recombination fraction (theta) of 0.00. Haplotype analysis further localized the LQT gene within a 6.2-cM interval. HERG encodes a potassium channel which has been mapped to this region. Single-strand conformational polymorphism analyses demonstrated aberrant bands that were unique to all affected individuals. DNA sequencing of the aberrant bands demonstrated a G to A substitution in all affected patients; this point mutation results in the substitution of a highly conserved valine residue with a methionine (V822M) in the cyclic nucleotide-binding domain of this potassium channel. The cosegregation of this distinct mutation with LQT demonstrates that HERG is the LQT gene in this pedigree. Furthermore, the location and character of this mutation suggests that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarization and may decrease susceptibility to ventricular tachyarrhythmias.

Adult↗
PubMed1999

Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.

Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.

Cation Transport Proteins↗
PubMed2000

Analysis of the human KCNH2(HERG) gene: identification and characterization of a novel mutation Y667X associated with long QT syndrome and a non-pathological 9 bp insertion.

Long QT (LQT) syndrome is a potentially life-threatening disorder, characterized by a distinct cardiac arrhythmia known as torsades de pointes. Mutations within a number of genes linked to the familial form, including that coding for a cardiac potassium channel called KCNH2 (HERG), have been described based on the characterized genomic organization. A standardized method was developed to screen the entire gene for gene variants. We report a single base pair substitution, introducing a premature STOP codon at codon 667 of the gene in a healthy individual with an extended QTc interval (460 msec). In vitro expression of the codon Y667X variant in Xenopus oocyte suggests that the autosomal dominant variant does not function in a dominant/negative manner and cannot co-assemble to form a channel, resulting in a reduction of the KCNH2 current, and an extension of the QT interval. This indicates that pathogenic LQT gene variants exist in the apparently normal population, the prognosis and clinical consequences of which remain to be determined. The assays described should facilitate future studies into this area.

Animals↗
PubMed2005

Voltage sensor movement in the hERG K+ channel.

The critical role of hERG in the maintenance of normal cardiac electrical activity derives from its unusual gating properties: slow channel activation and fast inactivation. To characterize voltage sensor movement associated with slow activation and fast inactivation, we measured gating currents from wild-type and mutant hERG channels. Fast and slow gating components were observed that differed 100-fold in their kinetics. The slow component constituted the majority of gating charge associated with channel opening and accounted for the sluggish rate of hERG activation. Gating currents from an inactivation-deficient mutant (S631A) were indistinguishable from wild-type, despite a +100 mV shift in the voltage dependence of inactivation, suggesting that a small fraction of total gating charge is devoted to the final transitions that inactivate the channel. Ala-scanning mutagenesis in S4 identified residues that perturbed both charge movement and channel opening. Residues in the S4-S5 linker perturbed channel opening without altering charge displacement, suggesting a role for coupling S4 movement to channel opening. Finally, inactivation-sensitive residues localized to a helical face of S4 adjacent to the activation-sensitive residues. We conclude that S4 acts as the voltage sensor for hERG activation and inactivation and that S4 movement is translated to the activation gate via the S4-S5 linker.

Animals↗
PubMed2001

Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG.

Long QT syndrome is a congenital disorder that presents with a defective cardiac ion channel and is either associated with prolonged action potential or, more commonly, known as an acquired form in which "torsades de pointes" type arrhythmias specifically occur after secondary causes. We report a case of a novel HERG mutation (A490T) that caused a bradycardia-associated form of long QT syndrome. A 27-year-old woman exhibited recurrent syncope due to torsades de pointes associated with a disturbance of the cardiac conduction system. By using polymerase chain reaction and single strand conformational polymorphism analyses, we identified a heterozygous single nucleotide substitution of HERG (G to A at nt 1468). This mutational change was not present in 140 Japanese control individuals. Electrophysiological assays for the A490T mutant HERG channel were conducted in the heterologous expression system with COS7 cells. The mutant channel was found to reconstitute functional channel currents, suggesting the homomeric mutant channel was functional. The mutation did not change the properties of the activation gate and inward rectification, however the current density of this mutant channel was small compared with that of wild type HERG. Taken together, this mutant may cause subtle changes in HERG channel functions (I(Kr)) in vivo. In this case, genetic background and unexpected bradycardia may have contributed to the development of long QT syndrome.

Adult↗
PubMed2000

Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N-terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20-30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals.

Adult↗
PubMed2002

A virtual screening method for prediction of the HERG potassium channel liability of compound libraries.

A computer-based method has been developed for prediction of the hERG (human ether-à-go-go related gene) K(+)-channel affinity of low molecular weight compounds. hERG channel blockage is a major concern in drug design, as such blocking agents can cause sudden cardiac death. Various techniques were applied to finding appropriate molecular descriptors for modeling structure-activity relationships: substructure analysis, self-organizing maps (SOM), principal component analysis (PCA), partial least squares fitting (PLS), and supervised neural networks. The most accurate prediction system was based on an artificial neural network. In a validation study, 93 % of the nonblocking agents and 71 % of the hERG channel blockers were correctly classified. This virtual screening method can be used for general compound-library shaping and combinatorial library design.

Cation Transport Proteins↗
PubMed2006

Protein distribution of Kcnq1, Kcnh2, and Kcne3 potassium channel subunits during mouse embryonic development.

Voltage-dependent potassium channels consist of a pore-forming alpha-subunit, which is modulated by additional beta-ancillary or regulatory subunits. Kcnq1 and Kcnh2 alpha-channel subunits play pivotal roles in the developing and adult heart. However, Kcnq1 and Kcnh2 have a much wider expression profile than strictly confined to the myocardium, similar to their putative regulatory Kcne1-5 beta-subunits. At present, the distribution of distinct potassium channel subunits has been partially mapped in adult tissues, whereas almost no information is available during embryonic development. In this study, we report a detailed analysis of Kcnq1, Kcnh2, and Kcne3 protein expression during mouse embryogenesis. Our results demonstrate that Kcnq1 and Kcnh2 are widely distributed. Coexpression of both alpha-subunits is observed in a wide variety of organs, such as heart and the skeletal muscle, whereas others display unique Kcnq1 or Knch2 expression. Interestingly, Kcne3 expression is also widely observed in distinct tissue layers during embryogenesis, supporting the notion that an exquisite balance of alpha- and beta-subunit expression is required for modulating potassium conductance in distinct organs and tissue layers.

Animals↗
PubMed2005

Phenytoin teratogenicity: hypoxia marker and effects on embryonic heart rhythm suggest an hERG-related mechanism.

BACKGROUND: The antiepileptic drug phenytoin (PHT) is a human and animal teratogen. The teratogenicity has been linked to PHT-induced embryonic cardiac arrhythmia and hypoxic damage during a period when regulation of embryonic heart rhythm is highly dependent on a specific K(+) ion current (I(Kr)). PHT has been shown to inhibit I(Kr). The aims of this study were to investigate whether teratogenic doses cause embryonic hypoxia during and after the I(Kr) susceptible period and to further characterize PHT effects on embryonic heart rhythm. METHODS: Pregnant C57BL mice were administered the hypoxia marker pimonidazole followed by PHT or saline (controls) on GD 10 or GD 15. The embryos were fixed and sectioned, and the immunostained sections were analyzed with a computer assisted image analysis. Effects of PHT (0-250 microM) on heart rhythm in GD 10 embryos cultured in vitro were videotaped and then analyzed by using a digitalization technique. RESULTS: PHT dose-dependently increased the hypoxia staining (6- and 11-fold after maternal dosing of 100 and 150 mg/kg, respectively) during the period I(Kr) is expressed and functional (GD 10). In contrast, there were no differences between the PHT doses in hypoxia staining, and much less pronounced hypoxia after this period (GD 15). With increasing PHT concentrations, increased length of the interval (bradycardia) and large variations in length between individual heartbeats (arrhythmia) were recorded. CONCLUSIONS: PHT induced bradycardia/arrhythmia and severe embryonic hypoxia during the I(Kr) susceptible period, supporting the idea of an I(Kr)-arrhythmia-hypoxia-related teratogenic mechanism.

Animals↗
PubMed2006

An accurate and interpretable bayesian classification model for prediction of HERG liability.

Drug-induced QT interval prolongation has been identified as a critical side-effect of non-cardiovascular therapeutic agents and has resulted in the withdrawal of many drugs from the market. As almost all cases of drug-induced QT prolongation can be traced to the blockade of a voltage-dependent potassium ion channel encoded by the hERG (the human ether-à-go-go-related gene), early identification of potential hERG channel blockers will decrease the risk of cardiotoxicity-induced attritions in the later and more expensive development stage. Presented herein is a naive Bayes classifier to categorize hERG blockers into active and inactive classes, by using a universal, generic molecular descriptor system.1 The naive Bayes classifier was built from a training set containing 1979 corporate compounds, and exhibited an ROC accuracy of 0.87. The model was validated on an external test set of 66 drugs, of which 58 were correctly classified. The cumulative probabilities reflected the confidence of prediction and were proven useful for the identification of hERG blockers. Relative performance was compared for two classifiers constructed from either an atom-type-based molecular descriptor or the long range functional class fingerprint descriptor FCFP_6. The combination of an atom-typing descriptor and the naive Bayes classification technique enables the interpretation of the resulting model, which offers extra information for the design of compounds free of undesirable hERG activity.

Bayes Theorem↗
PubMed2006

In silico classification of HERG channel blockers: a knowledge-based strategy.

The blockage of the hERG potassium channel by a wide number of diverse compounds has become a major pharmacological safety concern as it can lead to sudden cardiac death. In silico models can be potent tools to screen out potential hERG blockers as early as possible during the drug-discovery process. In this study, predictive models developed using the recursive partitioning method and created using diverse datasets from 203 molecules tested on the hERG channel are described. The first model was built with hERG compounds grouped into two classes, with a separation limit set at an IC50 value of 1 microm, and reaches an overall accuracy of 81%. The misclassification of molecules having a range of activity between 1 and 10 microM led to the generation of a tri-class model able to correctly classify high, moderate, and weak hERG blockers with an overall accuracy of 90%. Another model, constructed with the high and weak hERG-blocker categories, successfully increases the accuracy to 96%. The results reported herein indicate that a combination of precise, knowledge management resources and powerful modeling tools are invaluable to assessing potential cardiotoxic side effects related to hERG blockage.

Drug Design↗
PubMed2003

Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system.

Voltage-dependent K(+) channels play a pivotal role in controlling cellular excitability within the nervous system. The aim of the present study was to investigate the expression in the adult rat brain of the three ether-a-gogo-related gene (ERG) family members ERG1, ERG2, and ERG3, encoding for K(+) channel subunits. To this aim, the distribution of ERG transcripts was studied by means of reverse-transcription polymerase chain reaction (RT-PCR) and nonradioactive in situ hybridization histochemistry (NR-ISH). Furthermore, ERG1 subunit distribution was studied by immunohistochemical analysis. RT-PCR analysis revealed ERG1, ERG2, and ERG3 expression in the olfactory bulb, cerebral cortex, hippocampus, hypothalamus, and cerebellum. NR-ISH experiments detected transcripts encoded by all three ERG genes in the cerebral cortex and in all CA subfields and in the granular cell layer of the dentate gyrus of the hippocampus; strong ERG1 signals were also detected in scattered large elements throughout the oriens, pyramidal, and radiatum layers, and in the hilus of the dentate gyrus. In the thalamus, positively labeled neurons were detected in the reticular nucleus with ERG1 and ERG3 and in the anterodorsal nucleus with ERG2 riboprobes. Transcripts for ERG1 and, to a lesser degree, also for ERG3, were detected in the basal ganglia and in several brainstem nuclei. All three ERG genes appeared to be expressed in cerebellar Purkinje cells. Finally, ERG1 expression was also revealed in non-neuronal elements such as ependymal and subependymal cells along the ventricular walls and hippocampal astrocytes. These results suggest that the K(+) channel isoforms of the ERG family appear to be expressed in different central nervous system regions where they might differentially control the firing of neurons engaged in several networks.

Action Potentials↗
PubMed2005

Expression pattern of the ether-a-go-go-related (ERG) family proteins in the adult mouse central nervous system: evidence for coassembly of different subunits.

Voltage-dependent K+ channels are the main determinants in controlling cellular excitability within the central nervous system. Among voltage-dependent K+ channels, the ERG subfamily is deeply involved in the control of cellular excitability, both in mammals and in invertebrates. ERG channels are encoded by different genes: the erg1 gene, which can generate two alternative transcripts (erg1a and erg1b), erg2 and erg3. The aim of the present study was to determine the expression pattern and cellular localization of ERG proteins (ERG1, ERG2, and ERG3) in the mouse CNS, differentiating, for the first time, the ERG1A and ERG1B isoforms. To this purpose, novel specific antibodies were raised against the various channel proteins and their specificity and immunoreactivity tested. It emerged that: 1) all the erg genes were indeed translated in neuronal tissue; 2) ERG proteins distribution in the mouse CNS often overlapped, and only in specific areas each ERG protein showed a distinct pattern of expression; and 3) ERG proteins were generally expressed in neuronal soma, but dendritic and/or white matter labeling could be detected in specific areas. The finding that ERG proteins often have an overlapping expression suggests that neuronal ERG currents could be determined, at least in part, by heterotetrameric ERG channels. This suggestion is demonstrated to occur for ERG1A/ERG1B by showing that the two isoforms coassemble in mouse brain.

Animals↗
PubMed2002

DHPLC analysis of potassium ion channel genes in congenital long QT syndrome.

Congenital long QT syndrome (LQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). As a result of these arrhythmias, patients suffer from recurrent syncopes, seizures, or sudden death as the most dramatic event. Mutations in five genes, encoding cardiac ion channels, have been identified in LQTS. Two potassium-channel genes, KCNQ1 (LQT1) and KCNH2 (LQT2 or HERG), are frequently involved in LQTS. Potassium-channel defects account for approximately 50-60% of LQTS. As patients benefit from preventive medication, early detection of a genetic defect is desired to identify the family members at risk. Speed and sensitivity of mutation detection was improved by applying the denaturing high performance liquid chromatography (DHPLC) technique for analysis of the entire KCNQ1 and KCNH2 genes and the protein encoding part of the KCNE1 and KCNE2 genes. By using this methodology, seven missense mutations in the KCNQ1 gene and nine mutations (four missense, two nonsense, one insertion, and two deletions) in the KCNH2 gene have been identified in a total number of 32 index patients diagnosed with LQTS syndrome. We conclude that this method is suitable for rapid identification of LQT gene defects due to the combination of automation, high throughput, sensitivity, and short time of analysis.

Base Sequence↗
PubMed2001

Automated mutation screening using dideoxy fingerprinting and capillary array electrophoresis.

The rapid progress in the isolation of genes associated with human disease has resulted in an increasing demand for mutation screening methods. The molecular diagnosis of the long QT syndrome (LQTS), a cardiac disorder characterized by prolongation of the QT(c) interval in the ECG, syncopes, and sudden death, requires mutation screening of all exons in at least five genes, encoding cardiac Na(+) and K(+) channel subunits. A method for automated dideoxy fingerprinting (ddF) using capillary array electrophoresis (CAE) was developed and the efficiency of the method was tested by analyzing 24 DNA samples with mutations in one of the genes KCNQ1 and KCNH2, which are involved in 50% of LQTS cases. One of these mutations, 362insQK in KCNQ1, is novel. The sensitivity was 100% using a single electrophoresis temperature of 18 degrees C or 25 degrees C. However, analysis of the samples in both the sense and anti-sense direction were required for high sensitivity. Analysis in a single direction resulted in a decrease of the sensitivity to 74% and 70%, respectively. The throughput of the ddF method, if performed with a 16 capillary CAE instrument, is 288 samples per seven hr if each sample is analyzed on both strands.

Automation↗