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BACKGROUND: Genetic testing for cardiac channelopathies is the standard of care. However, many rare genetic variants remain classified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data. Whether deep protein language models may aid in VUS resolution remains unknown. Here, we set out to compare how 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-causative genes compared with the gold-standard patch clamp. METHODS: A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2, and 50 SCN5A) were engineered by site-directed mutagenesis and expressed in either HEK293 cells or TSA201 cells. Whole-cell patch-clamp technique was used to functionally characterize these variants. The protein language models, ESM1b and AlphaMissense, were used to predict the variant effect of missense variants and compared with patch clamp. RESULTS: Considering variants in all 3 genes, the ESM1b model had a receiver operator curve-area under the curve of 0.75 (P=0.0003). It had a sensitivity of 88% and a specificity of 50%. AlphaMissense performed well compared with patch-clamp with an receiver operator curve-area under the curve of 0.85 (P<0.0001), sensitivity of 80%, and specificity of 76%. CONCLUSIONS: Deep protein language models aid in VUS resolution with high sensitivity but lower specificity. Thus, these tools cannot fully replace functional characterization but can aid in reducing the number of variants that may require functional analysis.
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Introduction: Long QT syndrome (LQTS) is an autosomal dominant inherited cardiac condition characterized by a QT interval prolongation and risk of sudden death. There are 17 subtypes of this syndrome associated with genetic variants in 11 genes. The second most common is type 2, caused by a mutation in the KCNH2 gene, which is part of the potassium channel and influences the final repolarization of the ventricular action potential. This case report presents an Ecuadorian teen with congenital Long QT Syndrome type 2 (OMIM ID: 613688), from a family without cardiac diseases or sudden cardiac death backgrounds. Case presentation: A 14-year-old girl with syncope, normal echocardiogram, and an irregular electrocardiogram was diagnosed with LQTS. Moreover, by performing Next-Generation Sequencing, a pathogenic variant in the KCNH2 gene p.(Ala614Val) (ClinVar ID: VCV000029777.14) associated with LQTS type 2, and two variants of uncertain significance in the AKAP9 p.(Arg1654GlyfsTer23) (rs779447911), and TTN p. (Arg34653Cys) (ClinVar ID: VCV001475968.4) genes were identified. Furthermore, ancestry analysis showed a mainly Native American proportion. Conclusion: Based on the genomic results, the patient was identified to have a high-risk profile, and an implantable cardioverter defibrillator was selected as the best treatment option, highlighting the importance of including both the clinical and genomics aspects for an integral diagnosis.
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Background: Long QT syndrome (LQTS) is an inherited malignant arrhythmia syndrome that poses a risk of sudden death. Variants in the Potassium Voltage-Gated Channel Subfamily H Member 2 (KCNH2) gene are known to cause Long QT syndrome through an autosomal dominant inheritance pattern. However, as of now, there have been no reports of any KCNH2 variant leading to Long QT syndrome exhibiting incomplete penetrance that is influenced by gender. Methods: Whole-exome sequencing (WES) was conducted on the proband to identify pathogenic variants. Subsequently, Sanger sequencing was employed to validate the identified likely pathogenic variants in all family members. Results: We analyzed a pedigree spanning three-generations afflicted by Long QT syndrome. WES revealed a novel KCNH2 missense variant (p.Val630Gly, c.1889 T>G) as the causative factor for the family's phenotype. Within this family, all three male carriers of the KCNH2 variant carriers exhibited the Long QT syndrome phenotype: one experienced sudden death during sleep, another received an implantable cardioverter defibrillator (ICD), and a younger man displayed a prolonged QTc interval without any instances of syncope or malignant arrhythmia to date. Interestingly, the middle-aged female carrier showed no Long QT Syndrome phenotype. However, her offspring, diagnosed with Turner syndrome (45, X) and also a carrier of this variant, experienced frequent syncope starting at 12 years old and was diagnosed with Long QT syndrome, leading to an ICD implantation when she was 15 years old. These observations suggest that the manifestation of Long QT syndrome associated with this KCNH2 variant exhibits incomplete penetrance influenced by gender within this family, indicating potential protective mechanisms against the syndrome in females affected by this variant. Conclusion: Our investigation has led to the identification of a novel pathogenic KCNH2 variant responsible for Long QT syndrome within a familial context characterized by gender-selective, incomplete penetrance. This discovery highlights a unique pathogenic inheritance pattern for the KCNH2 gene associated with Long QT syndrome, and could potentially shed light on the distinct penetrance behaviors and patterns of the KCNH2 gene. This discovery broadens our exploration of the KCNH2 gene in cardiac arrhythmias, highlighting the intricate genetic dynamics behind Long QT syndrome.
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Sudden Cardiac Death (SCD) often shows negative anatomy results after a systemic autopsy and the gene mutations of potassium channel play a key role in the etiology of SCD. We established a feasible system to detect SCD-related mutations and investigated the mutations at KCNQ1 and KCNH2 genes in the Chinese population. We established a mutation detection system combined with multiplex PCR, SNaPshot technique, and capillary electrophoresis. We genotyped 101 putative mutations at KCNQ1 and KCNH2 genes in 60 SCD of negative anatomy and 50 controls using the established assay and compared Odd Ratio (OR). Four coding variants were identified in the KCNQ1 gene: S546S, I145I, P448R, and G643S. The mutations of I145I and S546S did not differ significantly in the SCD compared with controls. 21 SCD individuals (35 %) and 1 control individual (2 %) showed a genotype of C/G at P448R (OR = 17.5, 95 % CI [2.40-127.82]). 24 SCD individuals (40 %) and 1 control individual (2 %) showed a genotype of C/G at G643S (OR = 20.0, 95 % CI [2.75-145.25]). We established a robust assay for rapid screening the putative SCD-related mutations in KCNQ1 and KCNH2 genes. The new assay in our study is easily amenable to the majority of laboratories without the need for new specialized equipment. Our method will meet the increasing requirement of mutation screening for SCD in regular DNA laboratories and will help screen mutations in those dead of SCD and their relatives.
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Muerte Súbita Cardíaca , Canal de Potasio ERG1 , Genotipo , Canal de Potasio KCNQ1 , Mutación , Humanos , Canal de Potasio KCNQ1/genética , Muerte Súbita Cardíaca/etiología , Canal de Potasio ERG1/genética , Masculino , Estudios de Casos y Controles , Femenino , Adulto , Persona de Mediana Edad , Electroforesis Capilar , Pueblo Asiatico/genética , Reacción en Cadena de la Polimerasa Multiplex , Adulto Joven , Análisis Mutacional de ADN , AncianoRESUMEN
BACKGROUND: Long QT syndrome (LQTS) is a cardiac channelopathy characterized by impaired myocardial repolarization that predisposes to life-threatening arrhythmias. This study aimed to elucidate the genetic basis of LQTS in an affected Iranian family using whole exome sequencing (WES). METHODS: A 37-year-old woman with a personal and family history of sudden cardiac arrest and LQTS was referred for genetic study after losing her teenage daughter due to sudden cardiac death (SCD). WES was performed and variants were filtered and prioritized based on quality, allele frequency, pathogenicity predictions, and conservation scores. Sanger sequencing confirmed segregation in the family. RESULTS: WES identified a novel heterozygous frameshift variant (NM_000238.4:c.3257_3258insG; pGly1087Trpfs*32) in the KCNH2 encoding the α-subunit of the rapid delayed rectifier potassium channel responsible for cardiac repolarization. This variant, predicted to cause a truncated protein, is located in the C-terminal region of the channel and was classified as likely pathogenic based on ACMG guidelines. The variant was absent in population databases and unaffected family members. CONCLUSION: This study reports a novel KCNH2 frameshift variant in an Iranian family with LQTS, expanding the spectrum of disease-causing variants in this gene. Our findings highlight the importance of the C-terminal region in KCNH2 for proper channel function and the utility of WES in identifying rare variants in genetically heterogeneous disorders like LQTS. Functional characterization of this variant is warranted to fully elucidate its pathogenic mechanisms and inform personalized management strategies.
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Canal de Potasio ERG1 , Secuenciación del Exoma , Síndrome de QT Prolongado , Linaje , Humanos , Síndrome de QT Prolongado/genética , Canal de Potasio ERG1/genética , Femenino , Adulto , Mutación del Sistema de LecturaRESUMEN
Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.
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Síndrome de Brugada , Canal de Potasio ERG1 , Mutación con Ganancia de Función , Adulto , Animales , Humanos , Masculino , Persona de Mediana Edad , Síndrome de Brugada/genética , Síndrome de Brugada/metabolismo , Células CHO , Cricetulus , Electrocardiografía , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismo , Mutación MissenseRESUMEN
INTRODUCTION: Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy. AREAS COVERED: A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the ß1 subunit of integrin receptors. The hERG1/ß1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-ß1), which specifically targets the hERG1/ß1 integrin complex and exerts antineoplastic effects in preclinical experiments. EXPERT OPINION: Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/ß1 integrin complex through the bispecific antibody scDb-hERG1-ß1 can overcome such hindrances.
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Antineoplásicos , Integrina beta1 , Terapia Molecular Dirigida , Neoplasias , Humanos , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Integrina beta1/metabolismo , Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismoRESUMEN
BACKGROUND: Cardiac arrhythmia, a common cardiovascular disease, is closely related to genetic polymorphisms. However, the associations between polymorphisms in KCNH2 and various arrhythmias remain inadequately explored. METHODS: Guided by the assumption that KCNH2 genetic polymorphisms significantly contribute to the development of arrhythmias, we thoroughly explored the associations between 85 KCNH2 genetic variations and 16 cardiac arrhythmias in a sample obtained from the UK Biobank (UKBB, N = 307,473). The illnesses documented in the electronic medical records of the sample were mapped to a phecode system for a more accurate representation of distinct phenotypes. Survival analysis was used to test the effect of KCNH2 variants on arrhythmia incidence, and a phenotype-wide association study (PheWAS) was performed to investigate the effect of KCNH2 polymorphisms on 102 traits, including physical measurements, biomarkers, and hematological indicators. RESULTS: Novel associations of variants rs2269001 and rs7789585 in KCNH2 with paroxysmal tachycardia (PT) and atrial fibrillation/flutter (AF/AFL), respectively, were identified. Moreover, with an increase in the number of minor alleles of these two variants, the incidence rates of PT and AF/AFL decreased. In addition, the PheWAS results suggested that these two single nucleotide polymorphisms were associated with multiple parameters in physical measurements and neutrophil percentage. CONCLUSION: The multiple novel associations observed in this study illustrate the importance of KCNH2 genetic variations in the pathogenesis of arrhythmia.
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Fibrilación Atrial , Aleteo Atrial , Humanos , Fibrilación Atrial/genética , Aleteo Atrial/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Alelos , Canal de Potasio ERG1/genéticaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease characterized by severe pulmonary fibrosis, for which there is an urgent need for effective therapeutic agents. Mefloquine (Mef) is a quinoline compound primarily used for the treatment of malaria. However, high doses (>25 mg/kg) may lead to side effects such as cardiotoxicity and psychiatric disorders. Here, we found that low-dose Mef (5 mg/kg) can safely and effectively treat IPF mice. Functionally, Mef can improve the pulmonary function of IPF mice (PIF, PEF, EF50, VT, MV, PENH), alleviating pulmonary inflammation and fibrosis by inhibiting macrophage activity. Mechanically, Mef probably regulates the Jak2/Stat3 signaling pathway by binding to the 492HIS site of Potassium voltage-gated channel subfamily H member 2 (KCNH2) protein in macrophages, inhibiting the secretion of macrophage inflammatory and fibrotic factors. In summary, Mef may inhibit macrophage activity by binding to KCNH2 protein, thereby slowing down the progress of IPF.
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Fibrosis Pulmonar Idiopática , Mefloquina , Humanos , Ratones , Animales , Mefloquina/uso terapéutico , Macrófagos/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Pulmón/patología , Fibrosis , Transducción de Señal , Bleomicina/farmacología , Canal de Potasio ERG1/metabolismoRESUMEN
The c.453delC (p.Thr152Profs*14) frameshift mutation in KCNH2 is associated with an elevated risk of Long QT syndrome (LQTS) and fatal arrhythmia. Nevertheless, the loss-of-function mechanism underlying this mutation remains unexplored and necessitates an understanding of electrophysiology. To gain insight into the mechanism of the LQT phenotype, we conducted whole-cell patch-clamp and immunoblot assays, utilizing both a heterologous expression system and patient-derived induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) with 453delC-KCNH2. We also explored the site of translational reinitiation by employing LC/MS mass spectrometry. Contrary to the previous assumption of early termination of translation, the findings of this study indicate that the 453delC-KCNH2 leads to an N-terminally truncated hERG channel, a potential from a non-canonical start codon, with diminished expression and reduced current (IhERG). The co-expression with wildtype KCNH2 produced heteromeric hERG channel with mild dominant-negative effect. Additionally, the heterozygote patient-derived iPSC-CMs exhibited prolonged action potential duration and reduced IhERG, which was ameliorated with the use of a hERG activator, PD-118057. The results of our study offer novel insights into the mechanisms involved in congenital LQTS associated with the 453delC mutation of KCNH2. The mutant results in the formation of less functional N-terminal-truncated channels with reduced amount of membrane expression. A hERG activator is capable of correcting abnormalities in both the heterologous expression system and patient-derived iPSC-CMs.
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Células Madre Pluripotentes Inducidas , Síndrome de QT Prolongado , Humanos , Miocitos Cardíacos/metabolismo , Mutación del Sistema de Lectura , Células Madre Pluripotentes Inducidas/metabolismo , Canales de Potasio Éter-A-Go-Go/genética , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Heterocigoto , Mutación , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/metabolismoRESUMEN
BACKGROUND: Escitalopram can cause prolongation of the QT interval on the electrocardiogram (ECG). However, only some patients get pathological QTc prolongation in clinic. We investigated the influence of KCNQ1, KCNE1, and KCNH2 gene polymorphisms along with clinical factors on escitalopram-induced QTc prolongation. METHODS: A total of 713 patients prescribed escitalopram were identified and had at least one ECG recording in this retrospective study. 472 patients with two or more ECG data were divided into QTc prolongation (n = 119) and non-prolongation (n = 353) groups depending on the threshold change in QTc of 30 ms above baseline value (∆QTc ≥ 30 ms). 45 patients in the QTc prolongation group and 90 patients in the QTc non-prolongation group were genotyped for 43 single nucleotide polymorphisms (SNPs) of KCNQ1, KCNE1, and KCNH2 genes. RESULTS: Patients with QTc prolongation (∆QTc ≥ 30 ms) got higher escitalopram dose (10.3 mg) than patients without QTc prolongation (9.4 mg), although no significant relationship was found between QTc interval and escitalopram dose in the linear mixed model. Patients who were older/coronary disease/hypertension or carried with KCNE1 rs1805127 C allele, KCNE1 rs4817668 C allele, KCNH2 rs3807372 AG/GG genotype were significantly at risk for QTc prolongation (∆QTc ≥ 30 ms). Concomitant antipsychotic treatment was associated with a longer QTc interval. LIMITATIONS: A relatively small sample size and lack of the blood concentration of escitalopram restricted the accurate relationship between escitalopram dose and QTc interval. CONCLUSION: Our study revealed that KCNQ1, KCNE1, and KCNH2 gene polymorphisms along with clinical factors provide a complementary effect in escitalopram-induced QTc prolongation.
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Síndrome de QT Prolongado , Canales de Potasio con Entrada de Voltaje , Humanos , Escitalopram , Estudios Retrospectivos , Canal de Potasio KCNQ1/genética , Electrocardiografía , Polimorfismo de Nucleótido Simple , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/genética , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/efectos adversos , Canal de Potasio ERG1/genéticaRESUMEN
BACKGROUND: Among KCNH2 missense loss of function (LOF) variants, homozygosity -at any position in the Kv11.1/hERG channel - is very rare and generally leads to intrauterine death, while heterozygous variants in the pore are responsible for severe Type 2 long-QT syndrome (LQTS). We report a novel homozygous p.Gly603Ser missense variant in the pore of Kv11.1/hERG (KCNH2 c.1807G > A) discovered in the context of a severe LQTS. METHODS: We carried out a phenotypic family study combined with a functional analysis of mutated and wild-type (WT) Kv11.1 by two-electrode voltage-clamp using the Xenopus laevis oocyte heterologous expression system. RESULTS: The variant resulted in a severe LQTS phenotype (very prolonged corrected QT interval, T-wave alternans, multiple Torsades de pointes) with a delayed clinical expression in later childhood in the homozygous state, and in a Type 2 LQTS phenotype in the heterozygous state. Expression of KCNH2 p.Gly603Ser cRNA alone elicited detectable current in Xenopus oocytes. Inactivation kinetics and voltage dependence of activation were not significantly affected by the variant. The macroscopic slope conductance of the variant was three-fold less compared to the WT (18.5 ± 9.01 vs 54.7 ± 17.2 µS, p < 0.001). CONCLUSIONS: We characterized the novel p.Gly603Ser KCNH2 missense LOF variant in the pore region of Kv11.1/hERG leading to a severe but viable LQTS in the homozygous state and an attenuated Type 2 LQTS in heterozygous carriers. To our knowledge we provide the first description of a homozygous variant in the pore-forming region of Kv11.1 with a functional impact but a delayed clinical expression.
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Canal de Potasio ERG1 , Síndrome de QT Prolongado , Niño , Humanos , Canal de Potasio ERG1/genética , Síndrome de QT Prolongado/genética , Mutación Missense , Fenotipo , LinajeRESUMEN
The Kv11.1 potassium channel encoded by the Kcnh2 gene is crucial in conducting the rapid delayed rectifier K+ current in cardiomyocytes. Homozygous mutation in Kcnh2 is embryonically lethal in humans and mice. However, the molecular signaling pathway of intrauterine fetal loss is unclear. The present study generated a Kcnh2 knockout rat based on edited rat embryonic stem cells (rESCs). Kcnh2 knockout was embryonic lethal on day 11.5 of development due to a heart configuration defect. Experiments with human embryonic heart single cells (6.57 weeks postconception) suggested that potassium voltagegated channel subfamily H member 2 (KCNH2) plays a crucial role in the development of compact cardiomyocytes. By contrast, apoptosis was found to be triggered in the homozygous embryos, which could be attributed to the failure of KCNH2 to form a complex with integrin ß1 that was essential for preventing the process of apoptosis via inhibition of forkhead box O3A. Destruction of the KCNH2/integrin ß1 complex reduced the phosphorylation level of AKT and deactivated the glycogen synthase kinase 3 ß (GSK3ß)/ßcatenin pathway, which caused early developmental abnormalities in rats. The present work reveals a basic mechanism by which KCNH2 maintains intact embryonic heart development.
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Canal de Potasio ERG1 , Cardiopatías Congénitas , Animales , Femenino , Humanos , Ratones , Embarazo , Ratas , Desarrollo Embrionario , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Cardiopatías Congénitas/metabolismo , Integrina beta1/genética , Integrina beta1/metabolismo , Miocitos Cardíacos/metabolismoRESUMEN
Advances in next-generation sequencing have been exceptionally valuable for identifying variants in medically actionable genes. However, for most missense variants there is insufficient evidence to permit definitive classification of variants as benign or pathogenic. To overcome the deluge of Variants of Uncertain Significance, there is an urgent need for high throughput functional assays to assist with the classification of variants. Advances in parallel planar patch clamp technologies has enabled the development of automated high throughput platforms capable of increasing throughput 10- to 100-fold compared to manual patch clamp methods. Automated patch clamp electrophysiology is poised to revolutionize the field of functional genomics for inheritable cardiac ion channelopathies. In this review, we outline i) the evolution of patch clamping, ii) the development of high-throughput automated patch clamp assays to assess cardiac ion channel variants, iii) clinical application of these assays and iv) where the field is heading.
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A mutation to serine of a conserved threonine (T634S) in the hERG K+ channel S6 pore region has been identified as a variant of uncertain significance, showing a loss-of-function effect. However, its potential consequences for ventricular excitation and arrhythmogenesis have not been reported. This study evaluated possible functional effects of the T634S-hERG mutation on ventricular excitation and arrhythmogenesis by using multi-scale computer models of the human ventricle. A Markov chain model of the rapid delayed rectifier potassium current (IKr) was reconstructed for wild-type and T634S-hERG mutant conditions and incorporated into the ten Tusscher et al. models of human ventricles at cell and tissue (1D, 2D and 3D) levels. Possible functional impacts of the T634S-hERG mutation were evaluated by its effects on action potential durations (APDs) and their rate-dependence (APDr) at the cell level; and on the QT interval of pseudo-ECGs, tissue vulnerability to unidirectional conduction block (VW), spiral wave dynamics and repolarization dispersion at the tissue level. It was found that the T634S-hERG mutation prolonged cellular APDs, steepened APDr, prolonged the QT interval, increased VW, destablized re-entry and augmented repolarization dispersion across the ventricle. Collectively, these results imply potential pro-arrhythmic effects of the T634S-hERG mutation, consistent with LQT2.
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INTRODUCTION: Long QT Syndrome (LQTS) is an inherited disease with an abnormal electrical conduction system in the heart that can cause sudden death as a result of QT prolongation. LQT2 is the second most common subtype of LQTS caused by loss of function mutations in the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene. Although more than 900 mutations are associated with the LQTS, many of these mutations are not validated or characterized. METHODS AND RESULTS: Sequencing analyses of genomic DNA of a family with LQT2 identified a putative mutation. i.e., KCNH2(NM_000238.3): c.3099_3112del, in KCNH2 gene which appeared to be a definite pathogenic mutation. The family pedigree information showed a gender difference in clinical features and T-wave morphology between male and female patients. The female with mutation exhibited recurring ventricular arrhythmia and syncope, while two male carriers did not show any symptoms. In addition, T-wave in females was much flatter than in males. The female proband showed a positive reaction to the lidocaine test. Lidocaine injection almost completely blocked ventricular arrhythmia and shortened the QT interval by ≥30 ms. Treatment with propranolol, mexiletine, and implantation of cardioverter-defibrillators prevented the sustained ventricular tachycardia, ventricular fibrillation, and syncope, as assessed by a 3-year follow-up evaluation. CONCLUSIONS: A putative mutation c.3099_3112del in the KCNH2 gene causes LQT2 syndrome, and the pathogenic mutation mainly causes symptoms in female progeny.
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Canales de Potasio Éter-A-Go-Go , Síndrome de QT Prolongado , Humanos , Masculino , Femenino , Canales de Potasio Éter-A-Go-Go/genética , Canal de Potasio ERG1/genética , Factores Sexuales , Mutación/genética , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/diagnóstico , Síncope , LidocaínaRESUMEN
KCNH2 loss-of-function mutations cause long QT syndrome type 2 (LQT2), an inherited cardiac disorder associated with life-threatening ventricular arrhythmia. Through whole-exome sequencing, we discovered a novel AGCGACAC deletion (S981fs) in the hERG gene of an LQT2 patient. Using a heterologous expression system and patch clamping, we found that the mutant K channel had reduced cell surface expression and lower current amplitude compared to the wild type. However, functional expression was restored by lowering temperature and using potassium channel inhibitors or openers (E4031, cisapride, nicorandil). Co-immunoprecipitation experiments confirmed the assembly of mutant proteins with wild-type hERG. Confocal imaging showed decreased hERG distribution on the cell membrane in cells expressing S981fs. Notably, treatment with G418 significantly increased hERG current in wild-type/S981fs heterozygotes. In conclusion, our study identifies a novel hERG mutation leading to impaired Kv11.1 function due to trafficking and nonsense-mediated RNA decay defects. These findings shed light on the mechanisms underlying LQT2 and offer potential therapeutic avenues.
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Síndrome de QT Prolongado , Humanos , Secuenciación del Exoma , Síndrome de QT Prolongado/genética , Corazón , Membrana Celular , Mutación , Canal de Potasio ERG1/genéticaRESUMEN
Background: Long QT syndrome (LQTS) is a lethal cardiac condition. However, the clinical implementation of genetic testing has now made LQTS eminently treatable. Next-generation sequencing has remarkable potential for both clinical diagnostics and research of LQTS. Here, we investigated the genetic etiology in an LQTS-suspected Iranian pedigree by whole-exome sequencing and collected all KCNH2 variants with consensus based on publications. Methods: WES was performed on the proband of this pedigree to reveal the underlying cause of sudden cardiac death (SCD). The variant found was validated and segregated by polymerase chain reaction and Sanger sequencing. Based on the literature review, KCNH2 variants were retrospectively analyzed to identify pathogenic variants, likely pathogenic variants, and variants of uncertain significance by using different prediction tools. Results: WES identified an autosomal dominant nonsense variant, c.1425C>A: p.Tyr475Ter, in the KCNH2 gene, which appeared to be the most likely cause of LQTS in this pedigree. Moreover, our comprehensive literature review yielded 511 KCNH2 variants in association with the LQTS phenotype, with c.3002G>A (CADD Phred=49) being the most pathogenic variant. Conclusions: Variants in the KCNH2 gene are considered a major cause of LQTS worldwide. The detected c.1425C>A is a novel variant to be reported from Iran for the first time. This result indicates the importance of KCNH2 screening in a pedigree with SCD cases.