Journal articles: 'KCNH6 gene'

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Lu, Jing, Han Shen, Qi Li, Feng-Ran Xiong, Ming-Xia Yuan, and Jin-Kui Yang. "Effect of KCNH6 on Hepatic Endoplasmic Reticulum Stress and Glucose Metabolism." Hormone and Metabolic Research 52, no. 09 (August 4, 2020): 669–75. http://dx.doi.org/10.1055/a-1177-6814.

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AbstractAdult patients with a dysfunctional ether-a-go-go 2 (hERG2) protein, which is encoded by the KCNH6 gene, present with hyperinsulinemia and hyperglycemia. However, the mechanism of KCNH6 in glucose metabolism disorders has not been clearly defined. It has been proposed that sustained endoplasmic reticulum (ER) stress is closely concerned with hepatic insulin resistance and inflammation. Here, we demonstrate that Kcnh6 knockout (KO) mice had impaired glucose tolerance and increased levels of hepatic apoptosis, in addition to displaying an increased insulin resistance that was mediated by high ER stress levels. By contrast, overexpression of KCNH6 in primary hepatocytes led to a decrease in ER stress and apoptosis induced by thapsigargin. Similarly, induction of Kcnh6 by tail vein injection into KO mice improved glucose tolerance by reducing ER stress and apoptosis. Furthermore, we show that KCNH6 alleviated hepatic ER stress, apoptosis, and inflammation via the NFκB-IκB kinase (IKK) pathway both in vitro and in vivo. In summary, our study provides new insights into the causes of ER stress and subsequent induction of primary hepatocytes apoptosis.

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Zou, Anruo, Zhixin Lin, Margaret Humble, Christopher D. Creech, P. Kay Wagoner, Douglas Krafte, Timothy J. Jegla, and Alan D. Wickenden. "Distribution and functional properties of human KCNH8 (Elk1) potassium channels." American Journal of Physiology-Cell Physiology 285, no. 6 (December 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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Stecyk, Jonathan A. W., Christine S. Couturier, Denis V. Abramochkin, Diarmid Hall, Asia Arrant-Howell, Kerry L. Kubly, Shyanne Lockmann, et al. "Cardiophysiological responses of the air-breathing Alaska blackfish to cold acclimation and chronic hypoxic submergence at 5°C." Journal of Experimental Biology 223, no. 22 (October 5, 2020): jeb225730. http://dx.doi.org/10.1242/jeb.225730.

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ABSTRACTThe Alaska blackfish (Dallia pectoralis) remains active at cold temperatures when experiencing aquatic hypoxia without air access. To discern the cardiophysiological adjustments that permit this behaviour, we quantified the effect of acclimation from 15°C to 5°C in normoxia (15N and 5N fish), as well as chronic hypoxic submergence (6–8 weeks; ∼6.3–8.4 kPa; no air access) at 5°C (5H fish), on in vivo and spontaneous heart rate (fH), electrocardiogram, ventricular action potential (AP) shape and duration (APD), the background inward rectifier (IK1) and rapid delayed rectifier (IKr) K+ currents and ventricular gene expression of proteins involved in excitation–contraction coupling. In vivo fH was ∼50% slower in 5N than in 15N fish, but 5H fish did not display hypoxic bradycardia. Atypically, cold acclimation in normoxia did not induce shortening of APD or alter resting membrane potential. Rather, QT interval and APD were ∼2.6-fold longer in 5N than in 15N fish because outward IK1 and IKr were not upregulated in 5N fish. By contrast, chronic hypoxic submergence elicited a shortening of QT interval and APD, driven by an upregulation of IKr. The altered electrophysiology of 5H fish was accompanied by increased gene expression of kcnh6 (3.5-fold; Kv11.2 of IKr), kcnj12 (7.4-fold; Kir2.2 of IK1) and kcnj14 (2.9-fold; Kir2.4 of IK1). 5H fish also exhibited a unique gene expression pattern that suggests modification of ventricular Ca2+ cycling. Overall, the findings reveal that Alaska blackfish exposed to chronic hypoxic submergence prioritize the continuation of cardiac performance to support an active lifestyle over reducing cardiac ATP demand.

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Heida, Annejet, Lisette J. M. E. van der Does, Ahmed A. Y. Ragab, and 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 (June 20, 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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Ichise, Eisuke, Tomohiro Chiyonobu, Mitsuru Ishikawa, Yasuyoshi Tanaka, Mami Shibata, Takenori Tozawa, Yoshihiro Taura, et al. "Impaired neuronal activity and differential gene expression in STXBP1 encephalopathy patient iPSC-derived GABAergic neurons." Human Molecular Genetics 30, no. 14 (May 7, 2021): 1337–48. http://dx.doi.org/10.1093/hmg/ddab113.

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Abstract Syntaxin-binding protein 1 (STXBP1; also called MUNC18–1), encoded by STXBP1, is an essential component of the molecular machinery that controls synaptic vesicle docking and fusion. De novo pathogenic variants of STXBP1 cause a complex set of neurological disturbances, namely STXBP1 encephalopathy (STXBP1-E) that includes epilepsy, neurodevelopmental disorders and neurodegeneration. Several animal studies have suggested the contribution of GABAergic dysfunction in STXBP1-E pathogenesis. However, the pathophysiological changes in GABAergic neurons of these patients are still poorly understood. Here, we exclusively generated GABAergic neurons from STXBP1-E patient-derived induced pluripotent stem cells (iPSCs) by transient expression of the transcription factors ASCL1 and DLX2. We also generated CRISPR/Cas9-edited isogenic iPSC-derived GABAergic (iPSC GABA) neurons as controls. We demonstrated that the reduction in STXBP1 protein levels in patient-derived iPSC GABA neurons was slight (approximately 20%) compared to the control neurons, despite a 50% reduction in STXBP1 mRNA levels. Using a microelectrode array–based assay, we found that patient-derived iPSC GABA neurons exhibited dysfunctional maturation with reduced numbers of spontaneous spikes and bursts. These findings reinforce the idea that GABAergic dysfunction is a crucial contributor to STXBP1-E pathogenesis. Moreover, gene expression analysis revealed specific dysregulation of genes previously implicated in epilepsy, neurodevelopment and neurodegeneration in patient-derived iPSC GABA neurons, namely KCNH1, KCNH5, CNN3, RASGRF1, SEMA3A, SIAH3 and INPP5F. Thus, our study provides new insights for understanding the biological processes underlying the widespread neuropathological features of STXBP1-E.

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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, no. 3 (January 3, 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, and K. D. Keef. "Expression and function of KCNH2 (HERG) in the human jejunum." American Journal of Physiology-Gastrointestinal and Liver Physiology 284, no. 6 (June 1, 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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Stengel, Rayk, Eric Rivera-Milla, Nirakar Sahoo, Christina Ebert, Frank Bollig, Stefan H. Heinemann, Roland Schönherr, and Christoph Englert. "Kcnh1 Voltage-gated Potassium Channels Are Essential for Early Zebrafish Development." Journal of Biological Chemistry 287, no. 42 (August 27, 2012): 35565–75. http://dx.doi.org/10.1074/jbc.m112.363978.

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The Kcnh1 gene encodes a voltage-gated potassium channel highly expressed in neurons and involved in tumor cell proliferation, yet its physiological roles remain unclear. We have used the zebrafish as a model to analyze Kcnh1 function in vitro and in vivo. We found that the kcnh1 gene is duplicated in teleost fish (i.e. kcnh1a and kcnh1b) and that both genes are maternally expressed during early development. In adult zebrafish, kcnh1a and kcnh1b have distinct expression patterns but share expression in brain and testis. Heterologous expression of both genes in Xenopus oocytes revealed a strong conservation of characteristic functional properties between human and fish channels, including a unique sensitivity to intracellular Ca2+/calmodulin and modulation of voltage-dependent gating by extracellular Mg2+. Using a morpholino antisense approach, we demonstrate a strong kcnh1 loss-of-function phenotype in developing zebrafish, characterized by growth retardation, delayed hindbrain formation, and embryonic lethality. This late phenotype was preceded by transcriptional up-regulation of known cell-cycle inhibitors (p21, p27, cdh2) and down-regulation of pro-proliferative factors, including cyclin D1, at 70% epiboly. These results reveal an unanticipated basic activity of kcnh1 that is crucial for early embryonic development and patterning.

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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, and 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», no. 5(214) (May 29, 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, and 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, no. 5 (October 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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Larsen, Lars Allan, Paal Skytt Andersen, Jørgen Kanters, Ida Hastrup Svendsen, Joes Ramsøe Jacobsen, Jens Vuust, Göran Wettrell, Lisbeth Tranebjærg, Jørn Bathen, and 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, no. 8 (August 1, 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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Díaz, Lorenza, Samantha V. Bernadez-Vallejo, Rafael Vargas-Castro, Euclides Avila, Karla A. Gómez-Ceja, Rocío García-Becerra, Mariana Segovia-Mendoza, et al. "The Phytochemical α-Mangostin Inhibits Cervical Cancer Cell Proliferation and Tumor Growth by Downregulating E6/E7-HPV Oncogenes and KCNH1 Gene Expression." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 3055. http://dx.doi.org/10.3390/ijms24033055.

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Cervical cancer is the fourth most common cancer among women worldwide. The main factor associated with the onset and progression of this neoplasia is the human papillomavirus (HPV) infection. The HPV-oncogenes E6 and E7 are critical drivers of cellular transformation, promoting the expression of oncogenes such as KCNH1. The phytochemical α-mangostin (AM) is a potent antineoplastic and antiviral compound. However, its effects on HPV oncogenes and KCNH1 gene expression remain unknown. This study evaluated the effects of AM on cell proliferation, cell cycle distribution and gene expression, including its effects on tumor growth in xenografted mice. AM inhibited cell proliferation in a concentration-dependent manner, being the most sensitive cell lines those with the highest number of HPV16 copies. In addition, AM promoted G1-cell cycle arrest in CaSki cells, while led to cell death in SiHa and HeLa cells. Of interest was the finding of an AM-dependent decreased gene expression of E6, E7 and KCNH1 both in vitro and in vivo, as well as the modulation of cytokine expression, Ki-67, and tumor growth inhibition. On these bases, we suggest that AM represents a good option as an adjuvant for the treatment and prevention of cervical cancer.

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Lignon, Jacques M., Zoë Bichler, Bruno Hivert, François E. Gannier, Pierre Cosnay, José A. del Rio, Danièle Migliore-Samour, and Claire O. Malécot. "Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21." Physiological Genomics 33, no. 2 (April 2008): 230–39. http://dx.doi.org/10.1152/physiolgenomics.00143.2007.

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Congenital heart defects (CHD) are common in Down syndrome (DS, trisomy 21). Recently, cardiac sympathetic-parasympathetic imbalance has also been documented in DS adults free of any CHD. The KCNJ6 gene located on human chromosome 21 encodes for the Kir3.2/GIRK2 protein subunits of G protein-regulated K+ (KG) channels and could contribute to this altered cardiac regulation. To elucidate the role of its overexpression, we used homozygous transgenic (Tg+/+) mice carrying copies of human KCNJ6. These mice showed human Kir3.2 mRNA expression in the heart and a 2.5-fold increased translation in the atria. Phenotypic alterations were assessed by recording electrocardiogram of urethane anesthetized mice. Chronotropic responses to direct (carbachol) and indirect (methoxamine) muscarinic stimulation were enhanced in Tg+/+ mice with respect to wild-type (WT) mice. Alternating periods of slow and fast rhythm induced by CCPA (2-chloro- N-cyclopentyl-adenosine) were amplified in Tg+/+ mice, resulting in a reduced negative chronotropic effect. These drugs reduced the atrial P wave amplitude and area. P wave variations induced by methoxamine and CCPA were respectively increased and reduced in the Tg+/+ mice, while PR interval and ventricular wave showed no difference between Tg+/+ and WT. These results indicate that Tg+/+ mice incorporating the human KCNJ6 exhibit altered Kir3.2 expression and responses to drugs that would activate KG channels. Moreover, these altered expression and responses are limited to sino-atrial node and atria that normally express large amounts of KG channels. These data suggest that KCNJ6 could play an important role in altered cardiac regulation in DS patients.

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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, and Brian P. Delisle. "Long QT Syndrome Type 2: Emerging Strategies for Correcting Class 2 KCNH2 (hERG) Mutations and Identifying New Patients." Biomolecules 10, no. 8 (August 4, 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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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, no. 1 (November 21, 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, and 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, no. 4 (July 1, 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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Bruehl, Stephen, Jerod S. Denton, Daniel Lonergan, Mary Ellen Koran, Melissa Chont, Christopher Sobey, Shanik Fernando, William S. Bush, Puneet Mishra, and Tricia A. Thornton-Wells. "Associations between KCNJ6 (GIRK2) gene polymorphisms and pain-related phenotypes." Pain 154, no. 12 (December 2013): 2853–59. http://dx.doi.org/10.1016/j.pain.2013.08.026.

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Kamarajan, Chella, Ashwini K. Pandey, David B. Chorlian, Niklas Manz, Arthur T. Stimus, Howard J. Edenberg, Leah Wetherill, et al. "A KCNJ6 gene polymorphism modulates theta oscillations during reward processing." International Journal of Psychophysiology 115 (May 2017): 13–23. http://dx.doi.org/10.1016/j.ijpsycho.2016.12.007.

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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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Максимов, В. Н., Д. Е. Иванощук, П. С. Орлов, А. А. Иванова, С. К. Малютина, С. В. Максимова, И. А. Родина, О. В. Хамович, and В. П. Новосёлов. "The first results of gene panel sequencing in sudden cardiac death in young men." Nauchno-prakticheskii zhurnal «Medicinskaia genetika», no. 5(214) (May 29, 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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Bileišienė, Neringa, Jūratė Barysienė, Violeta Mikštienė, Eglė Preikšaitienė, Germanas Marinskis, Monika Keževičiūtė, Algirdas Utkus, and Audrius Aidietis. "Aborted Cardiac Arrest in LQT2 Related to Novel KCNH2 (hERG) Variant Identified in One Lithuanian Family." Medicina 57, no. 7 (July 16, 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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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, no. 12 (July 1, 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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Silva, Doroteia, Gabriel Miltenberger-Miltenyi, Maria José Correia, and António Nunes Diogo. "Novel mutation in the KCNH2 gene associated with long QT syndrome." Revista Portuguesa de Cardiologia 32, no. 2 (February 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, and António Nunes Diogo. "Novel mutation in the KCNH2 gene associated with long QT syndrome." Revista Portuguesa de Cardiologia (English Edition) 32, no. 2 (February 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, no. 4 (September 22, 2013): 554–59. http://dx.doi.org/10.1007/s00380-013-0406-2.

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Stump, Matthew R., Rachel T. Nguyen, Rachel H. Drgastin, Delaney Search, Qiuming Gong, and Zhengfeng Zhou. "Regulation of Kv11.1 Isoform Expression by Polyadenylate Binding Protein Nuclear 1." International Journal of Molecular Sciences 22, no. 2 (January 16, 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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Parent, Lucie. "A helical segment makes potassium channels go-go." Journal of Biological Chemistry 292, no. 18 (May 5, 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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Strehl, Sabine, Margit König, Katharina Spath, Markus Pisecker, and Georg Mann. "Juxtaposition of the BCL11B Gene to a Novel Region at 17q by a t(14;17)(q32;Q21) in Childhood T-Cell Lymphoblastic Lymphoma." Blood 110, no. 11 (November 16, 2007): 4130. http://dx.doi.org/10.1182/blood.v110.11.4130.4130.

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Abstract T-cell acute lymphoblastic lymphoma/leukemia is frequently associated with recurrent genetic aberrations that result in the deregulation of transcription factors. In this respect, BCL11B plays a key role in the differentiation and survival during T-cell development. The 3′-located regulatory elements of BCL11B are juxtaposed to TLX3 by a cryptic t(5;14)(q35;q32) in approximately 20% of childhood T-ALL, which leads to inappropriate expression of TLX3. BCL11B can also fuse to TRDC through an inv(14)(q11.2q32.31) resulting in the expression of a BCL11B-TRDC fusion transcript in the absence of wild-type BCL11B. Moreover, a t(6;14) involving BCL11B and the 6q26 region has been described. We have identified a novel BCL11B rearrangement in a case of childhood T-cell lymphoblastic lymphoma. Cytogenetics detected a t(14;17)(q32;q21) and subsequent FISH analysis using BCL11B-spanning and BCL11B 3′-breakpoint-cluster-region flanking BAC clones revealed that BCL11B itself was not disrupted. However, a translocation breakpoint downstream of the BCL11B was observed suggesting the activation of a juxtaposed gene usually residing at 17q by the transcriptional regulatory elements of BCL11B. To narrow down the breakpoint at 17q a FISH-based chromosome-walking strategy using a set of chromosome 17q-specific BACs was employed. A BAC clone encompassing - from centromere to telomere - the genes RAB5C (a member of the RAS oncogene family), KCNH4 (potassium voltage-gated channel, subfamily H (eag-related), member 4), HCRT (hypocretin (orexin) neuropeptide precursor), GHDC (GH3 domain containing; LGP1), STAT5B (signal transducer and activator of transcription 5B), and the 5′-end of STAT5A showed a split signal indicating that one of these genes was juxataposed to the BCL11B enhancer. RAB5C, KCNH4, GHDC, and STAT5B are transcribed in a telomere-centromere orientation, whereas STAT5A shows the opposite transcriptional direction. Together with the FISH pattern observed these data suggested that STAT5A was the most likely candidate gene that might be inappropriately expressed via the regulatory elements of BCL11B. However, semi-quantitative expression analysis showed that neither STAT5A nor STAT5B were significantly upregulated in the affected lymph node as compared to normal bone marrow, peripheral blood, and thymus. In fact, compared to the expression levels in the other tissues STAT5A seemed to be expressed at lower levels. Thus, also the expression levels of RAB5C, KCNH4, and GHDC were analyzed. KCNH4 expression was almost undetectable in bone marrow, peripheral blood, and thymus and for all three genes no elevated expression was observed in the T-cell lymphoma. Owing to the unchanged expression of these genes also the transcription level of STAT3, which is localized further distal to the breakpoint determined by FISH was analyzed, and similar to STAT5A showed lower expression. However, depletion of STATs usually results in reduced cell viability and apoptosis. Together, our data suggest several scenarios: rearrangements of the region containing the remote enhancer of BCL11B are not necessarily accompanied by high expression of a gene juxtaposed into the close vicinity, expression levels of the juxtaposed gene may be just modulated rather than strongly enhanced, the presence of a more complex translocation undetectable by cytogenetics that results in the overexpression of a gene not obviously affected by the translocation or the generation of a fusion gene.

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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, and 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, no. 13 (July 2, 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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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, no. 3 (March 2011): 433–41. http://dx.doi.org/10.1016/j.yjmcc.2010.11.017.

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Wang, Anna, Hongyan Guo, and Zaiqiu Long. "Integrative Analysis of Differently Expressed Genes Reveals a 17-Gene Prognosis Signature for Endometrial Carcinoma." BioMed Research International 2021 (July 14, 2021): 1–18. http://dx.doi.org/10.1155/2021/4804694.

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Endometrial carcinoma (EC) is the fifth widely occurring malignant neoplasm among women all over the world. However, there is still lacking efficacy indicators for EC’s prognosis. Here, we analyzed two databases including an RNA-sequencing-based TCGA dataset and a microarray-based GSE106191. After normalizing the raw data, we identified 114 common genes with upregulation and 308 common genes with downregulation in both the TCGA and GSE106191 databases. Bioinformatics analysis showed that the differently expressed genes in EC were related to the IL17 signaling pathway, PI3K-Akt signaling pathway, and cGMP-PKG signaling pathway. Furthermore, we performed the least absolute shrinkage and selection operator (LASSO) Cox regression analysis and generated a signature featuring 17 prognosis-related genes (MAL2, ANKRD22, METTL7B, IL32, ERFE, OAS1, TRPC1, SRPX, RAPGEF4, PSD3, SIMC1, TRPC6, WFS1, PGR, PAMR1, KCNK6, and FAM189A2) and found that it could predict OS in EC patients. The further analysis showed that OAS1, MAL2, ANKRD22, METTL7B, and IL32 were significantly upregulated in EC samples after comparison with normal samples. However, TRPC1, SRPX, RAPGEF4, PSD3, SIMC1, TRPC6, WFS1, PGR, PAMR1, KCNK6, and FAM189A2 were significantly downregulated in EC samples in comparison with normal samples. And correlation analysis showed that our results showed that the expressions of 17 prognosis-related hub genes were significantly correlated based on Pearson correlation. We here offer a newly genetic biomarker for the prediction of EC patients’ prognosis.

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Donner, Birgit C., Christoph Marshall, and 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, no. 3 (November 9, 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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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, and S. V. Maksimova. "The results of next-generation sequencing in men with borderline QT interval prolongation (pilot study)." Complex Issues of Cardiovascular Diseases 11, no. 2 (April 28, 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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Zamorano-León, José J., Rosa Yañez, Gabriel Jaime, Pablo Rodriguez-Sierra, Laura Calatrava-Ledrado, Roman R. Alvarez-Granada, Petra Jiménez Mateos-Cáceres, Carlos Macaya, and Antonio J. López-Farré. "KCNH2 Gene Mutation: A Potential Link Between Epilepsy and Long QT-2 Syndrome." Journal of Neurogenetics 26, no. 3-4 (April 19, 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, and J. Kevin Donahue. "Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation." Journal of Thoracic and Cardiovascular Surgery 154, no. 5 (November 2017): 1644–51. http://dx.doi.org/10.1016/j.jtcvs.2017.05.052.

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Tang, Xue, Juan Shao, and Xiaohong Qin. "Crystal structure of the PAS domain of the hEAG potassium channel." Acta Crystallographica Section F Structural Biology Communications 72, no. 8 (July 13, 2016): 578–85. http://dx.doi.org/10.1107/s2053230x16009419.

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KCNH voltage-gated potassium channels play critical roles in regulating cellular functions. The channel is composed of four subunits, each of which contains six transmembrane helices forming the central pore. The cytoplasmic parts of the subunits present a Per–Arnt–Sim (PAS) domain at the N-terminus and a cyclic nucleotide-binding homology domain at the C-terminus. PAS domains are conserved from prokaryotes to eukaryotes and are involved in sensing signals and cellular responses. To better understand the functional roles of PAS domains in KCNH channels, the structure of this domain from the humanether-à-go-gochannel (hEAG channel) was determined. By comparing it with the structures of theHomo sapiensEAG-related gene (hERG) channel and theDrosophilaEAG-like K+(dELK) channel and analyzing the structural features of the hEAG channel, it was identified that a hydrophobic patch on the β-sheet may mediate interaction between the PAS domain and other regions of the channel to regulate its functions.

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Nishizawa, Daisuke, Makoto Nagashima, Ryoji Katoh, Yasuo Satoh, Megumi Tagami, Shinya Kasai, Yasukazu Ogai, et al. "Association between KCNJ6 (GIRK2) Gene Polymorphisms and Postoperative Analgesic Requirements after Major Abdominal Surgery." PLoS ONE 4, no. 9 (September 16, 2009): e7060. http://dx.doi.org/10.1371/journal.pone.0007060.

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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, no. 7 (January 25, 2008): 907–14. http://dx.doi.org/10.1093/eurheartj/ehm619.

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Stoldere, Diāna, and Elīna Cimbolineca. "Surgical Approach in Congenital Long QT Interval Syndrome Patients." Acta Chirurgica Latviensis 18, no. 1 (November 18, 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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Baye, Jordan, Amanda Massmann, Natasha Petry, Joel Van Heukelom, Kristen De Berg, April Schultz, and 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, no. 20 (May 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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Miyake, A., S. Takahashi, Y. Nakamura, K. Inamura, S. i. Matsumoto, S. Mochizuki, and M. Katou. "Disruption of the Ether-a-go-go K+ Channel Gene BEC1/KCNH3 Enhances Cognitive Function." Journal of Neuroscience 29, no. 46 (November 18, 2009): 14637–45. http://dx.doi.org/10.1523/jneurosci.0901-09.2009.

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Kang, S. J., M. Rangaswamy, N. Manz, J. C. Wang, L. Wetherill, T. Hinrichs, L. Almasy, et al. "Family-based genome-wide association study of frontal theta oscillations identifies potassium channel gene KCNJ6." Genes, Brain and Behavior 11, no. 6 (May 31, 2012): 712–19. http://dx.doi.org/10.1111/j.1601-183x.2012.00803.x.

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Simons, Cas, Lachlan D. Rash, Joanna Crawford, Linlin Ma, Ben Cristofori-Armstrong, David Miller, Kelin Ru, et al. "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy." Nature Genetics 47, no. 1 (November 24, 2014): 73–77. http://dx.doi.org/10.1038/ng.3153.

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Yoshikane, Yukako, Masao Yoshinaga, Kunihiro Hamamoto, and 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, no. 4 (April 2013): 600–603. http://dx.doi.org/10.1016/j.hrthm.2012.12.008.

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Alshalalfa, Mohammed, Tarek A. Bismar, and Reda Alhajj. "Detecting Cancer Outlier Genes with Potential Rearrangement Using Gene Expression Data and Biological Networks." Advances in Bioinformatics 2012 (June 28, 2012): 1–13. http://dx.doi.org/10.1155/2012/373506.

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Gene alterations are a major component of the landscape of tumor genomes. To assess the significance of these alterations in the development of prostate cancer, it is necessary to identify these alterations and analyze them from systems biology perspective. Here, we present a new method (EigFusion) for predicting outlier genes with potential gene rearrangement. EigFusion demonstrated excellent performance in identifying outlier genes with potential rearrangement by testing it to synthetic and real data to evaluate performance. EigFusion was able to identify previously unrecognized genes such as FABP5 and KCNH8 and confirmed their association with primary and metastatic prostate samples while confirmed the metastatic specificity for other genes such as PAH, TOP2A, and SPINK1. We performed protein network based approaches to analyze the network context of potential rearranged genes. Functional gene rearrangement Modules are constructed by integrating functional protein networks. Rearranged genes showed to be highly connected to well-known altered genes in cancer such as AR, RB1, MYC, and BRCA1. Finally, using clinical outcome data of prostate cancer patients, potential rearranged genes demonstrated significant association with prostate cancer specific death.

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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 (July 2022): 38–47. http://dx.doi.org/10.1016/j.euroneuro.2022.04.012.

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Nishizawa, Daisuke, Ken-ichi Fukuda, Shinya Kasai, Yasukazu Ogai, Junko Hasegawa, Naomi Sato, Hidetaka Yamada, et al. "Association Between KCNJ6 (GIRK2) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence." Journal of Pharmacological Sciences 126, no. 3 (2014): 253–63. http://dx.doi.org/10.1254/jphs.14189fp.

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Harley, Carol A., Greg Starek, David K. Jones, Andreia S. Fernandes, Gail A. Robertson, and João H. Morais-Cabral. "Enhancement of hERG channel activity by scFv antibody fragments targeted to the PAS domain." Proceedings of the National Academy of Sciences 113, no. 35 (August 11, 2016): 9916–21. http://dx.doi.org/10.1073/pnas.1601116113.

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The human human ether-à-go-go–related gene (hERG) potassium channel plays a critical role in the repolarization of the cardiac action potential. Changes in hERG channel function underlie long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. A striking feature of this channel and KCNH channels in general is the presence of an N-terminal Per-Arnt-Sim (PAS) domain. In other proteins, PAS domains bind ligands and modulate effector domains. However, the PAS domains of KCNH channels are orphan receptors. We have uncovered a family of positive modulators of hERG that specifically bind to the PAS domain. We generated two single-chain variable fragments (scFvs) that recognize different epitopes on the PAS domain. Both antibodies increase the rate of deactivation but have different effects on channel activation and inactivation. Importantly, we show that both antibodies, on binding to the PAS domain, increase the total amount of current that permeates the channel during a ventricular action potential and significantly reduce the action potential duration recorded in human cardiomyocytes. Overall, these molecules constitute a previously unidentified class of positive modulators and establish that allosteric modulation of hERG channel function through ligand binding to the PAS domain can be attained.

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Journal articles on the topic 'KCNH6 gene'

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