Articles de revues : « KCNH2 gene »

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Heida, Annejet, Lisette J. M. E. van der Does, Ahmed A. Y. Ragab et Natasja M. S. de Groot. « A Rare Case of the Digenic Inheritance of Long QT Syndrome Type 2 and Type 6 ». Case Reports in Medicine 2019 (20 juin 2019) : 1–4. http://dx.doi.org/10.1155/2019/1384139.

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We report a 37-year-old woman with an out-of-hospital cardiac arrest caused by ventricular fibrillation due to digenic inheritance of long QT syndrome type 2 (KCNH2 gene) and type 6 (KCNE2 gene). During hospitalization, prolonged QTc intervals and frequent episodes of ventricular tachyarrhythmias manifested. Genetic testing identified a mutation of the KCNH2 gene and an unclassified variant, most likely pathogenic, of the KCNE2 gene. This digenic inheritance is extremely rare.

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Larsen, Lars Allan, Paal Skytt Andersen, Jørgen Kanters, Ida Hastrup Svendsen, Joes Ramsøe Jacobsen, Jens Vuust, Göran Wettrell, Lisbeth Tranebjærg, Jørn Bathen et Michael Christiansen. « Screening for Mutations and Polymorphisms in the Genes KCNH2 and KCNE2 Encoding the Cardiac HERG/MiRP1 Ion Channel : Implications for Acquired and Congenital Long Q-T Syndrome ». Clinical Chemistry 47, n^o 8 (1 août 2001) : 1390–95. http://dx.doi.org/10.1093/clinchem/47.8.1390.

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Abstract Background: The voltage-gated, rapid-delayed rectifier current (IKr) is important for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the α-subunit HERG and KCNE2 for the β-subunit MiRP1, cause acquired and congenital long Q-T syndrome (LQTS) and other cardiac arrhythmias. Methods: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The method was used to screen 40 unrelated LQTS patients. Results: Eleven mutations, of which six were novel, were found in KCNH2. Interestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing the need to examine the entire gene when screening for mutations. No mutations were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. Conclusions: The potential role of rare polymorphisms in the HERG/MiRP1 K+-channel should be clarified with respect to drug interactions and susceptibility to arrhythmia and sudden death.

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Максимов, В. Н., Д. Е. Иванощук, П. С. Орлов, А. А. Иванова, С. К. Малютина, С. В. Максимова, И. А. Родина, О. В. Хамович et В. П. Новосёлов. « The first results of gene panel sequencing in sudden cardiac death in young men ». Nauchno-prakticheskii zhurnal «Medicinskaia genetika», n^o 5(214) (29 mai 2020) : 36–38. http://dx.doi.org/10.25557/2073-7998.2020.05.36-38.

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Цель исследования: поиск причинных мутаций в генах-кандидатах внезапной сердечной смерти (ВСС) у мужчин, умерших в возрасте до 45 лет. Группа ВСС (30 образцов) была сформирована c использованием критериев ВСС ВОЗ и Европейского общества кардиологов. Средний возраст 31,3±5,3 года. Геномную ДНК выделяли из ткани миокарда методом фенол-хлороформной экстракции. Выполнили секвенирование клинического экзома. На первом этапе проанализировали результаты секевнирования 16 генов, мутации в которых приводят к ССЗ, ассоциированным с повышенным риском ВСС: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1, SCN10A. Из 30 образцов с ВСС при анализе результатов секвенирования 16 генов было обнаружено 6 вероятно патогенных миссенс-мутаций в 7 образцах (23,3 %). В гене SCN10A обнаружено 2 мутации, в KCNH2, KCNE1, AKAP9, SNTA1 - по одной мутации. Подводя первые итоги пилотного исследования ВСС можно сделать следующие предварительные выводы: необходимо продолжение исследований в области молекулярной аутопсии в России, для повышения результативности поиска причинных мутаций, желательны снижение возраста случаев ВСС включаемых в исследование, а также работа с семьями умерших ВСС. Objective: Search for causal mutations in candidate genes for sudden cardiac death (SCD) in men who die before the age of 45. Materials and methods. The SCD group (30 samples) was formed using the criteria for sudden cardiac death of the WHO and the European Society of Cardiology. The average age is 31,3±5,3 years. Genomic DNA was isolated from myocardial tissue using phenol-chloroform extraction. Clinical exome sequencing was performed. At the first stage, the results of sequencing of 16 genes were analyzed, mutations in which result in CVD associated with an increased risk of SCD: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNJ5, KCNJ5, SNTA1, SCN10A. Results. Of 30 samples with SCD, when analyzing the results of sequencing 16 genes, 6 probably pathogenic missense mutations were found in 7 samples (23.3%). 2 mutations were found in the SCN10A gene, one mutation in KCNH2, KCNE1, AKAP9, SNTA1. Findings. Summing up the first results of a pilot SCD study, the following preliminary conclusions can be drawn: it is necessary to continue research in the field of molecular autopsy in Russia, in order to increase the effectiveness of the search for causative mutations, it is desirable to reduce the age of SCD cases included in the study, as well as work with families of deceased SCD.

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Orlov, P. S., D. E. Ivanoshchuk, A. M. Nesterets, A. A. Kuznetsov, A. A. Ivanova, S. K. Maliutina, D. V. Denisova, E. V. Striukova, V. N. Maksimov et S. V. Maksimova. « The results of next-generation sequencing in men with borderline QT interval prolongation (pilot study) ». Complex Issues of Cardiovascular Diseases 11, n^o 2 (28 avril 2022) : 98–106. http://dx.doi.org/10.17802/2306-1278-2022-11-2-98-106.

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Highlights. Probably causal mutations of QT interval prolongation in genes associated with LQTS were found in men of the Siberian population.Aim. To detect and study mutations in individuals with borderline prolongation of the QT interval in Siberian males.Methods. The study was conducted on the material of the international project HAPIEE in the period from 2003 to 2005 and screening of young people aged 25–44, performed in Novosibirsk. The total sample of men was 1353 people aged 25 to 69 years. From each age subgroup (25–29, 30–34, ..., 65–69 years old) 2–3 samples with the highest QT values were selected . The study group consisted of 30 men who subsequently underwent sequencing of a panel of genes. The search for mutations was carried out in genes associated with long QT syndrome (LQTS): KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1, SCN4B, KCNJ5, ANK2, CAV3, SNTA1, AKAP9, CALM1 and CALM2. All identified single nucleotide variants were verified by direct Sanger sequencing.Results. Three rare variants in the LQTS genes have been identified: p.P197L of the KCNQ1 gene, p.R176W, and p.D1003GfsX116 of the KCNH2 gene.Conclusion. In Caucasian men from the Novosibirsk population with borderline prolongation of the QT interval, probably causal substitutions in the LQTS genes – KCNH2 and KCNQ1, contributing to the prolongation of the QT interval, were found. To clarify the spectrum and frequency of occurrence of various mutations in genes, life-threatening arrhythmias in the population, additional studies are needed on extended samples.

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Zou, Anruo, Zhixin Lin, Margaret Humble, Christopher D. Creech, P. Kay Wagoner, Douglas Krafte, Timothy J. Jegla et Alan D. Wickenden. « Distribution and functional properties of human KCNH8 (Elk1) potassium channels ». American Journal of Physiology-Cell Physiology 285, n^o 6 (décembre 2003) : C1356—C1366. http://dx.doi.org/10.1152/ajpcell.00179.2003.

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The Elk subfamily of the Eag K+ channel gene family is represented in mammals by three genes that are highly conserved between humans and rodents. Here we report the distribution and functional properties of a member of the human Elk K+ channel gene family, KCNH8. Quantitative RT-PCR analysis of mRNA expression patterns showed that KCNH8, along with the other Elk family genes, KCNH3 and KCNH4, are primarily expressed in the human nervous system. KCNH8 was expressed at high levels, and the distribution showed substantial overlap with KCNH3. In Xenopus oocytes, KCNH8 gives rise to slowly activating, voltage-dependent K+ currents that open at hyperpolarized potentials (half-maximal activation at -62 mV). Coexpression of KCNH8 with dominant-negative KCNH8, KCNH3, and KCNH4 subunits led to suppression of the KCNH8 currents, suggesting that Elk channels can form heteromultimers. Similar experiments imply that KCNH8 subunits are not able to form heteromultimers with Eag, Erg, or Kv family K+ channels.

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Caballero, Ricardo, Raquel G. Utrilla, Irene Amorós, Marcos Matamoros, Marta Pérez-Hernández, David Tinaquero, Silvia Alfayate et al. « Tbx20 controls the expression of the KCNH2 gene and of hERG channels ». Proceedings of the National Academy of Sciences 114, n^o 3 (3 janvier 2017) : E416—E425. http://dx.doi.org/10.1073/pnas.1612383114.

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Long QT syndrome (LQTS) exhibits great phenotype variability among family members carrying the same mutation, which can be partially attributed to genetic factors. We functionally analyzed the KCNH2 (encoding for Kv11.1 or hERG channels) and TBX20 (encoding for the transcription factor Tbx20) variants found by next-generation sequencing in two siblings with LQTS in a Spanish family of African ancestry. Affected relatives harbor a heterozygous mutation in KCNH2 that encodes for p.T152HfsX180 Kv11.1 (hERG). This peptide, by itself, failed to generate any current when transfected into Chinese hamster ovary (CHO) cells but, surprisingly, exerted “chaperone-like” effects over native hERG channels in both CHO cells and mouse atrial-derived HL-1 cells. Therefore, heterozygous transfection of native (WT) and p.T152HfsX180 hERG channels generated a current that was indistinguishable from that generated by WT channels alone. Some affected relatives also harbor the p.R311C mutation in Tbx20. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Tbx20 enhanced human KCNH2 gene expression and hERG currents (IhERG) and shortened action-potential duration (APD). However, Tbx20 did not modify the expression or activity of any other channel involved in ventricular repolarization. Conversely, p.R311C Tbx20 did not increase KCNH2 expression in hiPSC-CMs, which led to decreased IhERG and increased APD. Our results suggest that Tbx20 controls the expression of hERG channels responsible for the rapid component of the delayed rectifier current. On the contrary, p.R311C Tbx20 specifically disables the Tbx20 protranscriptional activity over KCNH2. Therefore, TBX20 can be considered a KCNH2-modifying gene.

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Farrelly, A. M., S. Ro, B. P. Callaghan, M. A. Khoyi, N. Fleming, B. Horowitz, K. M. Sanders et K. D. Keef. « Expression and function of KCNH2 (HERG) in the human jejunum ». American Journal of Physiology-Gastrointestinal and Liver Physiology 284, n^o 6 (1 juin 2003) : G883—G895. http://dx.doi.org/10.1152/ajpgi.00394.2002.

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Previous studies suggest that ether-a-go-go related gene (ERG) KCNH2 potassium channels contribute to the control of motility patterns in the gastrointestinal tract of animal models. The present study examines whether these results can be translated into a role in human gastrointestinal muscles. Messages for two different variants of the KCNH2 gene were detected: KCNH2 V1 human ERG (HERG) (28) and KCNH2 V2 (HERGUSO) (13). The amount of V2 message was greater than V1 in both human jejunum and brain. The base-pair sequence that gives rise to domains S3– S5 of the channel was identical to that previously published for human KCNH2 V1 and V2. KCNH2 protein was detected immunohistochemically in circular and longitudinal smooth muscle and enteric neurons but not in interstitial cells of Cajal. In the presence of TTX (10−6 M), atropine (10−6M). and l-nitroarginine (10−4 M) human jejunal circular muscle strips contracted phasically (9 cycles/min) and generated slow waves with superimposed spikes. Low concentrations of the KCNH2 blockers E-4031 (10−8 M) and MK-499 (3 × 10−8 M) increased phasic contractile amplitude and the number of spikes per slow wave. The highest concentration of E-4031 (10−6 M) produced a 10–20 mV depolarization, eliminated slow waves, and replaced phasic contractions with a small tonic contracture. E-4031 (10−6 M) did not affect [14C]ACh release from enteric neurons. We conclude that KCNH2 channels play a fundamental role in the control of motility patterns in human jejunum through their ability to modulate the electrical behavior of smooth muscle cells.

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Сивцев, А. А., Л. И. Свинцова, И. В. Плотникова, И. Ж. Жалсанова, А. Е. Постригань, Л. И. Минайчева, О. Ю. Джаффарова et Н. А. Скрябин. « Analysis of mutations spectrum in the KCNQ1, KCNH2 and SCN5A genes in patients with long QT syndrome using massively parallel sequencing ». Nauchno-prakticheskii zhurnal «Medicinskaia genetika», n^o 5(214) (29 mai 2020) : 20–22. http://dx.doi.org/10.25557/2073-7998.2020.05.20-22.

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Проведен поиск мутаций в генах KCNQ1, KCNH2 и SCN5A методом массового параллельного секвенирования (МПС) у 10 пациентов из 8 семей с диагнозом «синдром удлиненного интервала QT» (СУИQT). Для пробоподготовки использована методика целевого обогащения участков ДНК, относящихся к исследуемым генам. В результате проведенной работы выявлено 8 мутаций: 5 из них расположены в гене KCNQ1, 2 мутации - в гене KCNH2, 1 мутация - в гене SCN5A. Во всех случаях были найдены уникальные мутации, не повторяющиеся у неродственных пациентов. Результаты проведенной работы указывают на эффективность использования таргетных панелей для поиска генетических аномалий при СУИQT. We searched for mutations in the KCNQ1, KCNH2 and SCN5A genes using mass parallel sequencing (MPS) in 10 patients from 8 families with a diagnosis of “long QT syndrome” (LQTS). For sample preparation, we used the targeted enrichment of DNA regions method related to the studied genes. As a result of the work, 8 mutations were revealed: 5 of them are located in the KCNQ1 gene, 2 mutations in the KCNH2 gene, 1 mutation in the SCN5A gene. In all cases, we found unique mutations that did not recur in unrelated patients. The results of this work indicate the effectiveness of using targeted panels to search for genetic abnormalities in LQTS.

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O’Hare, Bailey J., C. S. John Kim, Samantha K. Hamrick, Dan Ye, David J. Tester et Michael J. Ackerman. « Promise and Potential Peril With Lumacaftor for the Trafficking Defective Type 2 Long-QT Syndrome-Causative Variants, p.G604S, p.N633S, and p.R685P, Using Patient-Specific Re-Engineered Cardiomyocytes ». Circulation : Genomic and Precision Medicine 13, n^o 5 (octobre 2020) : 466–75. http://dx.doi.org/10.1161/circgen.120.002950.

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Background: The KCNH2 -encoded Kv11.1 hERG (human ether-a-go-go related gene) potassium channel is a critical regulator of cardiomyocyte action potential duration (APD). The majority of type 2 long-QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, Food and Drug Administration-approved cystic fibrosis protein trafficking chaperone, lumacaftor, has been proposed as novel therapy for LQT2. Here, we test the efficacy of lumacaftor treatment in patient-specific induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) derived from 2 patients with known LQT2 trafficking defective mutations and a patient with novel KCNH2 variant, p.R685P. Methods: Patient-specific iPSC-CM models of KCNH2-G604S, KCNH2-N633S, and KCNH2-R685P were generated from 3 unrelated patients diagnosed with severe LQT2 (rate-corrected QT>500 ms). Lumacaftor efficacy was also tested by ANEPPS, FluoVolt, and ArcLight voltage dye-based APD90 measurements. Results: All 3 mutations were hERG trafficking defective in iPSC-CMs. While lumacaftor treatment failed to rescue the hERG trafficking defect in TSA201 cells, lumacaftor rescued channel trafficking for all mutations in the iPSC-CM model. All 3 mutations conferred a prolonged APD90 compared with control. While lumacaftor treatment rescued the phenotype of KCNH2-N633S and KCNH2-R685P, lumacaftor paradoxically prolonged the APD90 in KCNH2-G604S iPSC-CMs. Lumacaftor-mediated APD90 rescue was affected by rapidly activating delayed rectifier K+ current blocker consistent with the increase of rapidly activating delayed rectifier K+ current by lumacaftor is the underlying mechanism of the LQT2 rescue. Conclusions: While lumacaftor is an effective hERG channel trafficking chaperone and may be therapeutic for LQT2, we urge caution. Without understanding the functionality of the mutant channel to be rescued, lumacaftor therapy could be harmful.

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Polyak, Margarita E., Anna Shestak, Dmitriy Podolyak et Elena Zaklyazminskaya. « Compound heterozygous mutations in KCNJ2 and KCNH2 in a patient with severe Andersen-Tawil syndrome ». BMJ Case Reports 13, n^o 8 (août 2020) : e235703. http://dx.doi.org/10.1136/bcr-2020-235703.

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Andersen-Tawil syndrome (ATS) is a rare channelopathy, sometimes referred to as long QT syndrome type 7. ATS is an autosomal dominant disease predominantly caused by mutations in the KCNJ2 gene. Patients with ATS present with episodes of muscle weakness, arrythmias, including prolonged QT intervals, and various skeletal abnormalities. Unlike other channelopathies, ATS has a relatively mild clinical course and low risk of sudden cardiac death. In this study, we describe a female patient with typical symptoms of ATS with the addition of unusually severe arrhythmias. Extensive DNA testing was performed to find the possible cause of this unique presentation. In addition to a known mutation in KCNJ2, the patient carried a variant in KCNH2. The combination of genetic variants may lead to the severe clinical manifestation of ATS. Additional genetic information allowed accurate genetic counselling to be provided to the patient.

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Wang, Feng, Yang Liu, Hongtao Liao, Yumei Xue, Xianzhang Zhan, Xianhong Fang, Yuanhong Liang et al. « Genetic Variants on SCN5A, KCNQ1, and KCNH2 in Patients with Ventricular Arrhythmias during Acute Myocardial Infarction in a Chinese Population ». Cardiology 145, n^o 1 (21 novembre 2019) : 38–45. http://dx.doi.org/10.1159/000502833.

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Objective: Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. About half of sudden deaths from AMI are mainly because of malignant ventricular arrhythmias (VA) after AMI. The sodium channel gene SCN5A and potassium channel genes KCNQ1 and KCNH2 have been widely reported to be genetic risk factors for arrhythmia including Brugada syndrome and long QT syndrome (LQTS). A few studies reported the association of SCN5A variant with ventricular tachycardia (VT)/ventricular fibrillation (VF) complicating AMI. However, little is known about the role of KCNQ1 and KCNH2 in AMI with VA (AMI_VA). This study focuses on investigating the potential variants on SCN5A, KCNQ1, and KCNH2 contributing to AMI with VA in a Chinese population. Materials and Methods: In total, 139 patients with AMI_VA, and 337 patients with AMI only, were included. Thirty exonic sites were selected to be screened. Sanger sequencing was used to detect variants. A subsequent association study was also performed between AMI_VA and AMI. Results: Twelve variants [5 on KCNH2(NM_000238.3), 3 on KCNQ1(NM_000218.2), and 4 on SCN5A(NM_198056.2)] were identified in AMI_VA patients. Only 5 (KCNH2: c.2690A>C; KCNQ1: c.1927G>A, c.1343delC; SCN5A: c.1673A>G, c.3578G>A) of them are missense variants. Two (KCNQ1: c.1343delC and SCN5A: c.3578G>A) of the missense variants were predicted to be clinically pathogenic. All these variants were further genotyped in an AMI without VA group. The association study identified a statistically significant difference in genotype frequency of KCNH2: c.1539C>T and KCNH2: c.1467C>T between the AMI and AMI_VA groups. Moreover, 2 rare variants (KCNQ1: c.1944C>T and SCN5A: c.3621C>T) showed an elevated allelic frequency (more than 1.5-fold) in the AMI_VA group when compared to the AMI group. Conclusion: Twelve variants (predicting from benign/VUS to pathogenic) were identified on KCNH2, KCNQ1, and SCN5A in patients with AMI_VA. Genotype frequency comparison between AMI_VA and AMI identified 2 significant common variants on KCNH2. Meanwhile, the allelic frequency of 2 rare variants on KCNQ1 and SCN5A, respectively, were identified to be enriched in AMI_VA, although there was no statistical significance. The present study suggests that the ion-channel genes KCNH2, KCNQ1, and SCN5A may contribute to the pathogenesis of VA during AMI.

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Zhai, Yafei, Jinxin Miao, Ying Peng, Guangming Fang, Chuchu Wang, Yaohe Wang, Xiaoyan Zhao et Jianzeng Dong. « Discovery of Digenic Mutation, KCNH2 c.1898A >C and JUP c.916dupA, in a Chinese Family with Long QT Syndrome via Whole-Exome Sequencing ». Cardiovascular Innovations and Applications 4, n^o 4 (1 juillet 2020) : 257–67. http://dx.doi.org/10.15212/cvia.2019.0578.

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Long QT syndrome (LQTS), which is caused by an ion channel‐related gene mutation, is a malignant heart disease with a clinical course of a high incidence of ventricular fibrillation and sudden cardiac death in the young. Mutations in KCNH2 (which encodes potassium voltage-gated channel subfamily H member 2) are responsible for LQTS in many patients. Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing. The c.916dupA mutation in JUP (which encodes junction plakoglobin) is also discovered. Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy. The double mutation in the proband may help explain his severe clinical manifestations, such as sudden cardiac death at an early age. Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line, while the mutation in JUP came from his maternal line. The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias.

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Ono, Makoto, Don E. Burgess, Elizabeth A. Schroder, Claude S. Elayi, Corey L. Anderson, Craig T. January, Bin Sun, Kalyan Immadisetty, Peter M. Kekenes-Huskey et Brian P. Delisle. « Long QT Syndrome Type 2 : Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients ». Biomolecules 10, n^o 8 (4 août 2020) : 1144. http://dx.doi.org/10.3390/biom10081144.

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Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2.

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Bando, Sachiko, Takeshi Soeki, Toshiyuki Niki, Kenya Kusunose, Koji Yamaguchi, Yoshio Taketani, Iwase Takashi et al. « Congenital Long QT Syndrome with Compound Mutations in KCNH2 Gene ». Journal of Arrhythmia 27, Supplement (2011) : PJ3_044. http://dx.doi.org/10.4020/jhrs.27.pj3_044.

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Hayashi, Kenshi, Noboru Fujino, Katsuharu Uchiyama, Hidekazu Ino, Kenji Sakata, Tetsuo Konno, Eiichi Masuta et al. « Long QT syndrome and associated gene mutation carriers in Japanese children : results from ECG screening examinations ». Clinical Science 117, n^o 12 (1 juillet 2009) : 415–24. http://dx.doi.org/10.1042/cs20080528.

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LQTS (long QT syndrome) is caused by mutations in cardiac ion channel genes; however, the prevalence of LQTS in the general population is not well known. In the present study, we prospectively estimated the prevalence of LQTS and analysed the associated mutation carriers in Japanese children. ECGs were recorded from 7961 Japanese school children (4044 males; mean age, 9.9±3.0 years). ECGs were examined again for children who had prolonged QTc (corrected QT) intervals in the initial ECGs, and their QT intervals were measured manually. An LQTS score was determined according to Schwartz's criteria, and ion channel genes were analysed. In vitro characterization of the identified mutants was performed by heterologous expression experiments. Three subjects were assigned to a high probability of LQTS (3.5≤ LQTS score), and eight subjects to an intermediate probability (1.0< LQTS score ≤3.0). Genetic analysis of these II subjects identified three KCNH2 mutations (M124T, 547–553 del GGCGGCG and 2311–2332 del/ins TC). In contrast, no mutations were identified in the 15 subjects with a low probability of LQTS. Electrophysiological studies showed that both the M124T and the 547–553 del GGCGGCG KCNH2 did not suppress the wild-type KCNH2 channel in a dominant-negative manner. These results demonstrate that, in a random sample of healthy Japanese children, the prevalence of a high probability of LQTS is 0.038% (three in 7961), and that LQTS mutation carriers can be identified in at least 0.038% (one in 2653). Furthermore, large-scale genetic studies will be needed to clarify the real prevalence of LQTS by gene-carrier status, as it may have been underestimated in the present study.

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Bileišienė, Neringa, Jūratė Barysienė, Violeta Mikštienė, Eglė Preikšaitienė, Germanas Marinskis, Monika Keževičiūtė, Algirdas Utkus et Audrius Aidietis. « Aborted Cardiac Arrest in LQT2 Related to Novel KCNH2 (hERG) Variant Identified in One Lithuanian Family ». Medicina 57, n^o 7 (16 juillet 2021) : 721. http://dx.doi.org/10.3390/medicina57070721.

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Congenital long QT syndrome (LQTS) is a hereditary ion channelopathy associated with ventricular arrhythmia and sudden cardiac death starting from young age due to prolonged cardiac repolarization, which is represented by QT interval changes in electrocardiogram (ECG). Mutations in human ether-à-go-go related gene (KCNH2 (7q36.1), formerly named hERG) are responsible for Long QT syndrome type 2 (LQT2). LQT2 is the second most common type of LQTS. A resuscitated 31-year-old male with the diagnosis of LQT2 and his family are described. Sequencing analysis of their genomic DNA was performed. Amino acid alteration p.(Ser631Pro) in KCNH2 gene was found. This variant had not been previously described in literature, and it was found in three nuclear family members with different clinical course of the disease. Better understanding of genetic alterations and genotype-phenotype correlations aids in risk stratification and more effective management of these patients, especially when employing a trigger-specific approach to risk-assessment and individually tailored therapy.

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Stump, Matthew R., Rachel T. Nguyen, Rachel H. Drgastin, Delaney Search, Qiuming Gong et Zhengfeng Zhou. « Regulation of Kv11.1 Isoform Expression by Polyadenylate Binding Protein Nuclear 1 ». International Journal of Molecular Sciences 22, n^o 2 (16 janvier 2021) : 863. http://dx.doi.org/10.3390/ijms22020863.

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The Kv11.1 voltage-gated potassium channel, encoded by the KCNH2 gene, conducts the rapidly activating delayed rectifier current in the heart. KCNH2 pre-mRNA undergoes alternative polyadenylation to generate two C-terminal Kv11.1 isoforms in the heart. Utilization of a poly(A) signal in exon 15 produces the full-length, functional Kv11.1a isoform, while intron 9 polyadenylation generates the C-terminally truncated, nonfunctional Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO isoforms plays an important role in the regulation of Kv11.1 channel function. In this study, we tested the hypothesis that the RNA polyadenylate binding protein nuclear 1 (PABPN1) interacts with a unique 22 nt adenosine stretch adjacent to the intron 9 poly(A) signal and regulates KCNH2 pre-mRNA alternative polyadenylation and the relative expression of Kv11.1a C-terminal isoforms. We showed that PABPN1 inhibited intron 9 poly(A) activity using luciferase reporter assays, tandem poly(A) reporter assays, and RNA pulldown assays. We also showed that PABPN1 increased the relative expression level of the functional Kv11.1a isoform using RNase protection assays, immunoblot analyses, and patch clamp recordings. Our present findings suggest a novel role for the RNA-binding protein PABPN1 in the regulation of functional and nonfunctional Kv11.1 isoform expression.

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Silva, Doroteia, Gabriel Miltenberger-Miltenyi, Maria José Correia et António Nunes Diogo. « Novel mutation in the KCNH2 gene associated with long QT syndrome ». Revista Portuguesa de Cardiologia 32, n^o 2 (février 2013) : 163–64. http://dx.doi.org/10.1016/j.repc.2012.06.012.

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Silva, Doroteia, Gabriel Miltenberger-Miltenyi, Maria José Correia et António Nunes Diogo. « Novel mutation in the KCNH2 gene associated with long QT syndrome ». Revista Portuguesa de Cardiologia (English Edition) 32, n^o 2 (février 2013) : 163–64. http://dx.doi.org/10.1016/j.repce.2013.02.008.

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Bando, Sachiko, Takeshi Soeki, Tomomi Matsuura, Toshiyuki Niki, Takayuki Ise, Koji Yamaguchi, Yoshio Taketani et al. « Congenital long QT syndrome with compound mutations in the KCNH2 gene ». Heart and Vessels 29, n^o 4 (22 septembre 2013) : 554–59. http://dx.doi.org/10.1007/s00380-013-0406-2.

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Kekenes-Huskey, Peter M., Don E. Burgess, Bin Sun, Daniel C. Bartos, Ezekiel R. Rozmus, Corey L. Anderson, Craig T. January, Lee L. Eckhardt et Brian P. Delisle. « Mutation-Specific Differences in Kv7.1 (KCNQ1) and Kv11.1 (KCNH2) Channel Dysfunction and Long QT Syndrome Phenotypes ». International Journal of Molecular Sciences 23, n^o 13 (2 juillet 2022) : 7389. http://dx.doi.org/10.3390/ijms23137389.

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The electrocardiogram (ECG) empowered clinician scientists to measure the electrical activity of the heart noninvasively to identify arrhythmias and heart disease. Shortly after the standardization of the 12-lead ECG for the diagnosis of heart disease, several families with autosomal recessive (Jervell and Lange-Nielsen Syndrome) and dominant (Romano–Ward Syndrome) forms of long QT syndrome (LQTS) were identified. An abnormally long heart rate-corrected QT-interval was established as a biomarker for the risk of sudden cardiac death. Since then, the International LQTS Registry was established; a phenotypic scoring system to identify LQTS patients was developed; the major genes that associate with typical forms of LQTS were identified; and guidelines for the successful management of patients advanced. In this review, we discuss the molecular and cellular mechanisms for LQTS associated with missense variants in KCNQ1 (LQT1) and KCNH2 (LQT2). We move beyond the “benign” to a “pathogenic” binary classification scheme for different KCNQ1 and KCNH2 missense variants and discuss gene- and mutation-specific differences in K+ channel dysfunction, which can predispose people to distinct clinical phenotypes (e.g., concealed, pleiotropic, severe, etc.). We conclude by discussing the emerging computational structural modeling strategies that will distinguish between dysfunctional subtypes of KCNQ1 and KCNH2 variants, with the goal of realizing a layered precision medicine approach focused on individuals.

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Parent, Lucie. « A helical segment makes potassium channels go-go ». Journal of Biological Chemistry 292, n^o 18 (5 mai 2017) : 7706–7. http://dx.doi.org/10.1074/jbc.h117.779298.

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More than 500 variants in the KCNH2 gene, which encodes the cardiac human ether-a-go-go (hERG) ion channel, have been associated with sudden cardiac death, but only a subset of these variants have been investigated. Matthew D. Perry and colleagues now combine NMR spectroscopy and electrophysiological experiments to explore the functional properties of mutations within an overlooked hERG helix, finding important contributions to channel function.

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Sun, Yaxun, Xiao-Qing Quan, Samantha Fromme, Robert H. Cox, Ping Zhang, Li Zhang, Donglin Guo et al. « A novel mutation in the KCNH2 gene associated with short QT syndrome ». Journal of Molecular and Cellular Cardiology 50, n^o 3 (mars 2011) : 433–41. http://dx.doi.org/10.1016/j.yjmcc.2010.11.017.

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Donner, Birgit C., Christoph Marshall et Klaus G. Schmidt. « A presumably benign human ether-a-go-go-related gene mutation (R176W) with a malignant primary manifestation of long QT syndrome ». Cardiology in the Young 22, n^o 3 (9 novembre 2011) : 360–63. http://dx.doi.org/10.1017/s1047951111001831.

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AbstractA 12-year-old girl presented with a first prolonged syncope. She was successfully resuscitated by external defibrillation after recording torsade de pointes tachycardia. Repeated electrocardiograms and a 12-channel Holter monitoring showed an intermittent prolongation of the QT interval. Genetic analysis identified a heterozygous point mutation in the KCNH2 gene, which is thought to be associated with a rather mild clinical phenotype of the long QT syndrome.

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Finley, Melissa R., Yan Li, Fei Hua, James Lillich, Kathy E. Mitchell, Suhasini Ganta, Robert F. Gilmour et Lisa C. Freeman. « Expression and coassociation of ERG1, KCNQ1, and KCNE1 potassium channel proteins in horse heart ». American Journal of Physiology-Heart and Circulatory Physiology 283, n^o 1 (1 juillet 2002) : H126—H138. http://dx.doi.org/10.1152/ajpheart.00622.2001.

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In dogs and in humans, potassium channels formed by ether-a-go-go-related gene 1 protein ERG1 (KCNH2) and KCNQ1 α-subunits, in association with KCNE β-subunits, play a role in normal repolarization and may contribute to abnormal repolarization associated with long QT syndrome (LQTS). The molecular basis of repolarization in horse heart is unknown, although horses exhibit common cardiac arrhythmias and may receive drugs that induce LQTS. In horse heart, we have used immunoblotting and immunostaining to demonstrate the expression of ERG1, KCNQ1, KCNE1, and KCNE3 proteins and RT-PCR to detect KCNE2 message. Peptide N-glycosidase F-sensitive forms of horse ERG1 (145 kDa) and KCNQ1 (75 kDa) were detected. Both ERG1 and KCNQ1 coimmunoprecipitated with KCNE1. Cardiac action potential duration was prolonged by antagonists of either ERG1 (MK-499, cisapride) or KCNQ1/KCNE1 (chromanol 293B). Patch-clamp analysis confirmed the presence of a slow delayed rectifier current. These data suggest that repolarizing currents in horses are similar to those of other species, and that horses are therefore at risk for acquired LQTS. The data also provide unique evidence for coassociation between ERG1 and KCNE1 in cardiac tissue.

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Zamorano-León, José J., Rosa Yañez, Gabriel Jaime, Pablo Rodriguez-Sierra, Laura Calatrava-Ledrado, Roman R. Alvarez-Granada, Petra Jiménez Mateos-Cáceres, Carlos Macaya et Antonio J. López-Farré. « KCNH2 Gene Mutation : A Potential Link Between Epilepsy and Long QT-2 Syndrome ». Journal of Neurogenetics 26, n^o 3-4 (19 avril 2012) : 382–86. http://dx.doi.org/10.3109/01677063.2012.674993.

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Liu, Zhao, Julie A. Hutt, Barur Rajeshkumar, Yoshihiro Azuma, Kailai L. Duan et J. Kevin Donahue. « Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation ». Journal of Thoracic and Cardiovascular Surgery 154, n^o 5 (novembre 2017) : 1644–51. http://dx.doi.org/10.1016/j.jtcvs.2017.05.052.

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Si, Man, Krystle Trosclair, Kathryn A. Hamilton et Edward Glasscock. « Genetic ablation or pharmacological inhibition of Kv1.1 potassium channel subunits impairs atrial repolarization in mice ». American Journal of Physiology-Cell Physiology 316, n^o 2 (1 février 2019) : C154—C161. http://dx.doi.org/10.1152/ajpcell.00335.2018.

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Voltage-gated Kv1.1 potassium channel α-subunits, encoded by the Kcna1 gene, have traditionally been regarded as neural-specific with no expression or function in the heart. However, recent data revealed that Kv1.1 subunits are expressed in atria where they may have an overlooked role in controlling repolarization and arrhythmia susceptibility independent of the nervous system. To explore this concept in more detail and to identify functional and molecular effects of Kv1.1 channel impairment in the heart, atrial cardiomyocyte patch-clamp electrophysiology and gene expression analyses were performed using Kcna1 knockout ( Kcna1−/−) mice. Specifically, we hypothesized that Kv1.1 subunits contribute to outward repolarizing K+ currents in mouse atria and that their absence prolongs cardiac action potentials. In voltage-clamp experiments, dendrotoxin-K (DTX-K), a Kv1.1-specific inhibitor, significantly reduced peak outward K+ currents in wild-type (WT) atrial cells but not Kcna1−/− cells, demonstrating an important contribution by Kv1.1-containing channels to mouse atrial repolarizing currents. In current-clamp recordings, Kcna1−/− atrial myocytes exhibited significant action potential prolongation which was exacerbated in right atria, effects that were partially recapitulated in WT cells by application of DTX-K. Quantitative RT-PCR measurements showed mRNA expression remodeling in Kcna1−/− atria for several ion channel genes that contribute to the atrial action potential including the Kcna5, Kcnh2, and Kcnj2 potassium channel genes and the Scn5a sodium channel gene. This study demonstrates a previously undescribed heart-intrinsic role for Kv1.1 subunits in mediating atrial repolarization, thereby adding a new member to the already diverse collection of known K+ channels in the heart.

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Sinner, Moritz F., Arne Pfeufer, Mahmut Akyol, Britt-Maria Beckmann, Martin Hinterseer, Annette Wacker, Siegfried Perz et al. « The non-synonymous coding IKr-channel variant KCNH2-K897T is associated with atrial fibrillation : results from a systematic candidate gene-based analysis of KCNH2 (HERG) ». European Heart Journal 29, n^o 7 (25 janvier 2008) : 907–14. http://dx.doi.org/10.1093/eurheartj/ehm619.

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Baye, Jordan, Amanda Massmann, Natasha Petry, Joel Van Heukelom, Kristen De Berg, April Schultz et Catherine Hajek. « Development and early evaluation of clinical decision support for long QT syndrome population screening ». Journal of Translational Genetics and Genomics 6 (2022) : 375–87. http://dx.doi.org/10.20517/jtgg.2022.12.

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Aim: Long QT syndrome (LQTS) is an inherited condition that predisposes individuals to prolongation of the QT interval and increased risk for Torsade de Pointes. Pathogenic variants in three genes - KCNH2, KCNQ1 and SCN5A - are responsible for most cases of LQTS, and recent advances in genetic testing have improved knowledge of the disease, increased access to follow-up, and reduced adverse cardiovascular outcomes. Methods: Based around our preemptive genetic screening platform which includes the three long QT genes listed above, we developed and implemented a clinical decision support (CDS) module that alerts prescribers whenever a QT-prolonging medication is ordered for patients with a genetic predisposition to LQTS. Results: Of the 13,777 individuals screened, twenty-seven tested positive for a pathogenic or likely pathogenic variant of KCNH2, KCNQ1 or SCN5A. In a subsequent early evaluation of the CDS and clinical processes, the number of QT-prolonging medications in this cohort decreased by 20% and new QT-prolonging medications were avoided in approximately 1/3 of new prescription orders. Conclusions: While long-term evaluation is needed, early data support the benefit of utilizing CDS in expanded roles, such as drug-gene-disease interactions where rare genetic variants intersect with everyday prescribing.

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Hocker, James D., Olivier B. Poirion, Fugui Zhu, Justin Buchanan, Kai Zhang, Joshua Chiou, Tsui-Min Wang et al. « Cardiac cell type–specific gene regulatory programs and disease risk association ». Science Advances 7, n^o 20 (mai 2021) : eabf1444. http://dx.doi.org/10.1126/sciadv.abf1444.

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Misregulated gene expression in human hearts can result in cardiovascular diseases that are leading causes of mortality worldwide. However, the limited information on the genomic location of candidate cis-regulatory elements (cCREs) such as enhancers and promoters in distinct cardiac cell types has restricted the understanding of these diseases. Here, we defined >287,000 cCREs in the four chambers of the human heart at single-cell resolution, which revealed cCREs and candidate transcription factors associated with cardiac cell types in a region-dependent manner and during heart failure. We further found cardiovascular disease–associated genetic variants enriched within these cCREs including 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Additional functional studies revealed that two of these variants affect a cCRE controlling KCNH2/HERG expression and action potential repolarization. Overall, this atlas of human cardiac cCREs provides the foundation for illuminating cell type–specific gene regulation in human hearts during health and disease.

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Armaganijan, L. « Mutação L955V no exon 12 do gene KCNH2 em paciente com síndrome do QT longo ». Revista Iberoamericana de Arritmología 4 (2013) : 16–20. http://dx.doi.org/10.5031/v4i1.ria10209.

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Stoldere, Diāna, et Elīna Cimbolineca. « Surgical Approach in Congenital Long QT Interval Syndrome Patients ». Acta Chirurgica Latviensis 18, n^o 1 (18 novembre 2020) : 63–69. http://dx.doi.org/10.2478/chilat-2020-0016.

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SummaryLong QT syndrome is a genetically determined clinical condition that can lead to sudden cardiac death, life–threatening arrhythmias, typically ventricular tachycardia – Torsades de Pointes in young, otherwise healthy, adults and children.Congenital long QT syndrome is the most common cause of sudden death in young adults with structurally normal heart.There are several studies, which introduce us to gene mutation types, responsible for this disease. At this point 17 types of LQTS gene mutations are recognized, most patients present with the first 3 LQTS gene mutations: KCNQ1, KCNH2, and SCN5A.Secondary factors like electrolyte disbalance, dietary restrictions, and specific drugs may also cause QT interval prolongation. It is important to rule out avoidable causes, before further evaluation of congenital disease.Several treatment options are used in daily practice, which also includes a surgical approach.Although not so often used and seen, surgical technique has positive results – recognized by both doctors and patients.

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Terrenoire, Cecile, Kai Wang, Kelvin W. Chan Tung, Wendy K. Chung, Robert H. Pass, Jonathan T. Lu, Jyh-Chang Jean et al. « Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics ». Journal of General Physiology 141, n^o 1 (31 décembre 2012) : 61–72. http://dx.doi.org/10.1085/jgp.201210899.

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Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na+ channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na+ channel current (INaL) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of INaL such that increasing the pacing rate markedly reduces INaL and, in addition, increases its inhibition by the Na+ channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband’s iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.

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Guardiola-Ripoll, Maria, Carmen Almodóvar-Payá, Alba Lubeiro, Raymond Salvador, Pilar Salgado-Pineda, Jesús J. Gomar, Amalia Guerrero-Pedraza et al. « New insights of the role of the KCNH2 gene in schizophrenia : An fMRI case-control study ». European Neuropsychopharmacology 60 (juillet 2022) : 38–47. http://dx.doi.org/10.1016/j.euroneuro.2022.04.012.

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Yoshikane, Yukako, Masao Yoshinaga, Kunihiro Hamamoto et Shinichi Hirose. « A case of long QT syndrome with triple gene abnormalities : Digenic mutations in KCNH2 and SCN5A and gene variant in KCNE1 ». Heart Rhythm 10, n^o 4 (avril 2013) : 600–603. http://dx.doi.org/10.1016/j.hrthm.2012.12.008.

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Pedersen, Philip Juul, Kirsten Brolin Thomsen, Emma Rie Olander, Frank Hauser, Maria de los Angeles Tejada, Kristian Lundgaard Poulsen, Soren Grubb, Rikke Buhl, Kirstine Calloe et Dan Arne Klaerke. « Molecular Cloning and Functional Expression of the Equine K+ Channel KV11.1 (Ether à Go-Go-Related/KCNH2 Gene) and the Regulatory Subunit KCNE2 from Equine Myocardium ». PLOS ONE 10, n^o 9 (16 septembre 2015) : e0138320. http://dx.doi.org/10.1371/journal.pone.0138320.

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AL-Eitan, Laith, Islam Al-Dalalah, Afrah Elshammari, Wael Khreisat et Ayah Almasri. « The Impact of Potassium Channel Gene Polymorphisms on Antiepileptic Drug Responsiveness in Arab Patients with Epilepsy ». Journal of Personalized Medicine 8, n^o 4 (14 novembre 2018) : 37. http://dx.doi.org/10.3390/jpm8040037.

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This study aims to investigate the effects of the three potassium channel genes KCNA1, KCNA2, and KCNV2 on increased susceptibility to epilepsy as well as on responsiveness to antiepileptic drugs (AEDs). The pharmacogenetic and case-control cohort (n = 595) consisted of 296 epileptic patients and 299 healthy individuals. Epileptic patients were recruited from the Pediatric Neurology clinic at the Queen Rania Al Abdullah Hospital (QRAH) in Amman, Jordan. A custom platform array search for genetic association in Jordanian-Arab epileptic patients was undertaken. The MassARRAY system (iPLEX GOLD) was used to genotype seven single nucleotide polymorphisms (SNPs) within three candidate genes (KCNA1, KCNA2, and KCNV2). Only one SNP in KCNA2, rs3887820, showed significant association with increased risk of susceptibility to generalized myoclonic seizure (p-value < 0.001). Notably, the rs112561866 polymorphism of the KCNA1 gene was non-polymorphic, but no significant association was found between the KCNA1 (rs2227910, rs112561866, and rs7974459) and KCNV2 (rs7029012, rs10967705, and rs10967728) polymorphisms and disease susceptibility or drug responsiveness among Jordanian patients. This study suggests that a significant association exists between the KCNA2 SNP rs3887820 and increased susceptibility to generalized myoclonic seizure. However, the present findings indicate that the KCNA1 and KCNV2 SNPs do not influence disease susceptibility and drug responsiveness in epileptic patients. Pharmacogenetic and case-control studies involving a multicenter and multiethnic approach are needed to confirm our results. To improve the efficacy and safety of epilepsy treatment, further studies are required to identify other genetic factors that contribute to susceptibility and treatment outcome.

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Ovali, M. A., et M. Uzun. « The effects of melatonin administration on KCNQ and KCNH2 gene expressions and QTc interval in pinealectomised rats ». Cellular and Molecular Biology 63, n^o 3 (31 mars 2016) : 45. http://dx.doi.org/10.14715/cmb/2017.63.3.9.

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Eddy, Carey-Anne, Judith M. MacCormick, Seo-Kyung Chung, Jackie R. Crawford, Donald R. Love, Mark I. Rees, Jonathan R. Skinner et Andrew N. Shelling. « Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome ». Heart Rhythm 5, n^o 9 (septembre 2008) : 1275–81. http://dx.doi.org/10.1016/j.hrthm.2008.05.033.

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Anson, Blake D., Michael J. Ackerman, David J. Tester, Melissa L. Will, Brian P. Delisle, Corey L. Anderson et Craig T. January. « Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels ». American Journal of Physiology-Heart and Circulatory Physiology 286, n^o 6 (juin 2004) : H2434—H2441. http://dx.doi.org/10.1152/ajpheart.00891.2003.

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Long QT syndrome (LQTS) is a cardiac repolarization disorder that can lead to arrhythmias and sudden death. Chromosome 7-linked inherited LQTS (LQT2) is caused by mutations in human ether-a-go-go-related gene ( HERG; KCNH2), whereas drug-induced LQTS is caused primarily by HERG channel block. Many common polymorphisms are functionally silent and have been traditionally regarded as benign and without physiological consequence. However, the identification of common nonsynonymous single nucleotide polymorphisms (nSNPs; i.e., amino-acid coding variants) with functional phenotypes in the SCN5A Na+ channel and MiRP1 K+ channel β-subunit have challenged this viewpoint. In this report, we test the hypothesis that common missense HERG polymorphisms alter channel physiology. Comprehensive mutational analysis of HERG was performed on genomic DNA derived from a population-based cohort of sudden infant death syndrome and two reference allele cohorts derived from 100 African American and 100 Caucasian individuals. Amino acid-encoding variants were considered common polymorphisms if they were present in at least two of the three study cohorts with an allelic frequency >0.5%. Four nSNPs were identified: K897T, P967L, R1047L, and Q1068R. Wild-type (WT) and polymorphic channels were heterologously expressed in human embryonic kidney cells, and biochemical and voltage-clamp techniques were used to characterize their functional properties. All channel types were processed similarly, but several electrophysiological differences were identified: 1) K897T current density was lower than the other polymorphic channels; 2) K897T channels activated at more negative potentials than WT and R1047L; 3) K897T and Q1068R channels inactivated and recovered from inactivation faster than WT, P967L, and R1047L channels; and 4) K897T channels showed subtle differences compared with WT channels when stimulated with an action potential waveform. In contrast to K897T and Q1068R channels, P967L and R1047L channels were electrophysiologically indistinguishable from WT channels. All HERG channels had similar sensitivity to block by cisapride. Therefore, some HERG polymorphic channels are electrophysiologically different from WT channels.

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Park, Jong Keun, Yong-Seog Oh, Jee-hyun Choi et Sungjoo Kim Yoon. « Single Nucleotide Deletion Mutation of KCNH2 Gene is Responsible for LQT Syndrome in a 3-Generation Korean Family ». Journal of Korean Medical Science 28, n^o 9 (2013) : 1388. http://dx.doi.org/10.3346/jkms.2013.28.9.1388.

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Tanaka, Yoshihiro, Kenshi Hayashi, Noboru Fujino, Tetsuo Konno, Hayato Tada, Chiaki Nakanishi, Akihiko Hodatsu et al. « Functional analysis of KCNH2 gene mutations of type 2 long QT syndrome in larval zebrafish using microscopy and electrocardiography ». Heart and Vessels 34, n^o 1 (25 juillet 2018) : 159–66. http://dx.doi.org/10.1007/s00380-018-1231-4.

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Giustetto, Carla, Chiara Scrocco, Daniela Giachino, Claudio Rapezzi, Barbara Mognetti et Fiorenzo Gaita. « The lack of effect of sotalol in short QT syndrome patients carrying the T618I mutation in the KCNH2 gene ». HeartRhythm Case Reports 1, n^o 5 (septembre 2015) : 373–78. http://dx.doi.org/10.1016/j.hrcr.2015.07.001.

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VERKERK, A., R. WILDERS, E. SCHULZEBAHR, L. BEEKMAN, Z. BHUIYAN, J. BERTRAND, L. ECKARDT, D. LIN, M. BORGGREFE et G. BREITHARDT. « Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome ». Cardiovascular Research 68, n^o 3 (1 décembre 2005) : 441–53. http://dx.doi.org/10.1016/j.cardiores.2005.06.027.

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Wojdyła-Hordyńska, Agnieszka, Grzegorz Hordyński, Patrycja Pruszkowska-Skrzep et Oskar Kowalski. « TRIGGER ABLATION IN LONG QT TYPE 2 PATIENT ». In a good rythm 1, n^o 46 (22 mars 2018) : 28–30. http://dx.doi.org/10.5604/01.3001.0011.6496.

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Implantable cardioverter-defibrillator (ICD) is an indicated therapy for Long QT (LQT) patients after syncope or cardiac arrest survival. Premature ventricular contractions (PVCs) triggers ablation is also a known, yet, still rare, method aiming at ventricular tachycardia or torsade de pointes treatment in LQT syndrome. We present a 21-year-old female with no previous medical history admitted after syncope during cycling. Family history revealed sudden cardiac death in a 36-year-old father of the patient. Genetic test presented a puntiform mutation of KCNH2 gene. Beta-blocker and life vest therapy were introduced. Three months later the patient was admitted due to presyncopy and documented polymorphic ventricular tachycardia initiated by premature ventricular contractions. The clinical PVC triggers ablation was performed and cardioverter-defibrillator implanted. The PVC in the left aortic cusp was successfully ablated, and an ICD was implanted to utilise an atrial pacing. During the next 12-months follow up no VTs were recorded.

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Andrsova, Irena, Tomas Novotny, Jitka Kadlecova, Alexandra Bittnerova, Pavel Vit, Alena Florianova, Martina Sisakova, Renata Gaillyova, Lenka Manouskova et Jindrich Spinar. « Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations : importance of exercise testing ». Journal of Electrocardiology 45, n^o 6 (novembre 2012) : 746–51. http://dx.doi.org/10.1016/j.jelectrocard.2012.05.004.

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Zamorano-León, José J., Sergio Alonso-Orgaz, Javier Moreno, Rafael Cinza, Maria J. García-Torrent, Nicasio Pérez-Castellano, Julián Pérez-Villacastín, Carlos Macaya et Antonio J. López-Farré. « Novel mutation (H402R) in the S1 domain of KCNH2-encoded gene associated with long QT syndrome in a Spanish family ». International Journal of Cardiology 142, n^o 2 (juillet 2010) : 206–8. http://dx.doi.org/10.1016/j.ijcard.2008.11.166.

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Liu, Li, Kenshi Hayashi, Tomoya Kaneda, Hidekazu Ino, Noboru Fujino, Katsuharu Uchiyama, Tetsuo Konno et al. « A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome ». Heart Rhythm 10, n^o 1 (janvier 2013) : 61–67. http://dx.doi.org/10.1016/j.hrthm.2012.09.053.

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Kałużna, Sandra, Mariusz J. Nawrocki, Karol Jopek, Greg Hutchings, Bartłomiej Perek, Marek Jemielity, Bartosz Kempisty, Agnieszka Malińska, Paul Mozdziak et Michał Nowicki. « In search of markers useful for evaluation of graft patency - molecular analysis of ‘muscle system process’ for internal thoracic artery and saphenous vein conduits ». Medical Journal of Cell Biology 8, n^o 1 (29 avril 2020) : 12–23. http://dx.doi.org/10.2478/acb-2020-0002.

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AbstractCoronary artery bypass graft (CABG) is the surgical method most commonly used to treat coronary artery disease (CAD). The vessels that are used in CABG are usually the internal thoracic artery (ITA) and the saphenous vein (SV). Transplant patency is one of the most important factors affecting transplant success. In this study, we used an expressive microarray method, approved by RT-qPCR, for transcriptome analysis of arterial and venous grafts. In the search for potential molecular factors, we analyzed gene ontologies of different expression based on the muscular system. Among interesting groups, we distinguished muscle cell proliferation, muscle contraction, muscle system process, regulation of smooth muscle cell proliferation and smooth muscle cell proliferation. The highest increase in gene expression was observed in: ACTN2, RBPMS2, NR4A3, KCNA5, while the smallest decrease in expression was shown by the P2RX1, KCNH2, DES and MYOT genes. Particularly noteworthy are the ACTN2 and NR4A3 genes, which can have a significant impact on vascular patency. ACTN2 is a gene that can affect the formation of atherosclerotic plaques, while NR4A3 occurs in 4 of the 5 ontological groups discussed and can affect the inflammatory process in the blood vessel. To summarize, the presented study provided valuable insight into the molecular aspects characterizing the vessels used in CABG, and in particular identified genes that may be the target for further studies on duct patency.Running title: CABG grafts’ molecular analysis of ‘muscle system process’

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