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Journal articles on the topic 'KCNA7 gene'

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Author: Grafiati

Published: 10 March 2023

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1

Angi, Beatrice, Silvia Muccioli, Ildikò Szabò, and Luigi Leanza. "A Meta-Analysis Study to Infer Voltage-Gated K+ Channels Prognostic Value in Different Cancer Types." Antioxidants 12, no. 3 (February 24, 2023): 573. http://dx.doi.org/10.3390/antiox12030573.

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Potassium channels are often highly expressed in cancer cells with respect to healthy ones, as they provide proliferative advantages through modulating membrane potential, calcium homeostasis, and various signaling pathways. Among potassium channels, Shaker type voltage-gated Kv channels are emerging as promising pharmacological targets in oncology. Here, we queried publicly available cancer patient databases to highlight if a correlation exists between Kv channel expression and survival rate in five different cancer types. By multiple gene comparison analysis, we found a predominant expression of KCNA2, KCNA3, and KCNA5 with respect to the other KCNA genes in skin cutaneous melanoma (SKCM), uterine corpus endometrial carcinoma (UCEC), stomach adenocarcinoma (STAD), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). This analysis highlighted a prognostic role of KCNA3 and KCNA5 in SKCM, LUAD, LUSC, and STAD, respectively. Interestingly, KCNA3 was associated with a positive prognosis in SKCM and LUAD but not in LUSC. Results obtained by the analysis of KCNA3-related differentially expressed genes (DEGs); tumor immune cell infiltration highlighted differences that may account for such differential prognosis. A meta-analysis study was conducted to investigate the role of KCNA channels in cancer using cancer patients’ datasets. Our study underlines a promising correlation between Kv channel expression in tumor cells, in infiltrating immune cells, and survival rate.

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2

Kashuba, Vladimir I., Sergei M. Kvasha, Alexei I. Protopopov, Rinat Z. Gizatullin, Alla V. Rynditch, Claes Wahlestedt, Wyeth W. Wasserman, and Eugene R. Zabarovsky. "Initial isolation and analysis of the human Kv1.7 ( KCNA7 ) gene, a member of the voltage-gated potassium channel gene family." Gene 268, no. 1-2 (May 2001): 115–22. http://dx.doi.org/10.1016/s0378-1119(01)00423-1.

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3

AL-Eitan, Laith, Islam Al-Dalalah, Afrah Elshammari, Wael Khreisat, and Ayah Almasri. "The Impact of Potassium Channel Gene Polymorphisms on Antiepileptic Drug Responsiveness in Arab Patients with Epilepsy." Journal of Personalized Medicine 8, no. 4 (November 14, 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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4

Bardien-Kruger, Soraya, Heike Wulff, Zainu Arieff, Paul Brink, K. George Chandy, and Valerie Corfield. "Characterisation of the human voltage-gated potassium channel gene, KCNA7, a candidate gene for inherited cardiac disorders, and its exclusion as cause of progressive familial heart block I (PFHBI)." European Journal of Human Genetics 10, no. 1 (January 2002): 36–43. http://dx.doi.org/10.1038/sj.ejhg.5200739.

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5

Si, Man, Krystle Trosclair, Kathryn A. Hamilton, and 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, no. 2 (February 1, 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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Brevnova, Elena E., Oleksandr Platoshyn, Shen Zhang, and Jason X. J. Yuan. "Overexpression of human KCNA5 increases IK(V) and enhances apoptosis." American Journal of Physiology-Cell Physiology 287, no. 3 (September 2004): C715—C722. http://dx.doi.org/10.1152/ajpcell.00050.2004.

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Apoptotic cell shrinkage, an early hallmark of apoptosis, is regulated by K+ efflux and K+ channel activity. Inhibited apoptosis and downregulated K+ channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in development of pulmonary vascular medial hypertrophy and pulmonary hypertension. The objective of this study was to test the hypothesis that overexpression of KCNA5, which encodes a delayed-rectifier voltage-gated K+ (Kv) channel, increases K+ currents and enhances apoptosis. Transient transfection of KCNA5 caused 25- to 34-fold increase in KCNA5 channel protein level and 24- to 29-fold increase in Kv channel current ( IK(V)) at +60 mV in COS-7 and rat PASMC, respectively. In KCNA5-transfected COS-7 cells, staurosporine (ST)-mediated increases in caspase-3 activity and the percentage of cells undergoing apoptosis were both enhanced, whereas basal apoptosis (without ST stimulation) was unchanged compared with cells transfected with an empty vector. In rat PASMC, however, transfection of KCNA5 alone caused marked increase in basal apoptosis, in addition to enhancing ST-mediated apoptosis. Furthermore, ST-induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K+ currents through KCNA5 channels and inhibited ST-induced apoptosis in KCNA5-transfected COS-7 cells. Overexpression of the human KCNA5 gene increases K+ currents (i.e., K+ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis. Induction of apoptosis in PASMC by KCNA5 gene transfer may serve as an important strategy for preventing the progression of pulmonary vascular wall thickening and for treating patients with idiopathic pulmonary arterial hypertension (IPAH).

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Fountain, Samuel J., Alex Cheong, Jing Li, Naciye Y. Dondas, Fanning Zeng, Ian C. Wood, and David J. Beech. "Kv1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 5 (November 2007): H2719—H2725. http://dx.doi.org/10.1152/ajpheart.00637.2007.

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KV1.5, a voltage-gated potassium channel, has functional importance in regulating blood vessel tone and cardiac action potentials and is a target for numerous therapeutic drug development programs. Despite the importance of KV1.5, there is little knowledge of the mechanisms controlling expression of its underlying gene, Kcna5. We identified a 5′ flanking region of the murine Kcna5 gene that drives expression of a luciferase reporter gene in primary smooth muscle cells and a smooth muscle cell line. The promoter contained CACCC nucleotide motifs, which we have shown to bind the Sp1 transcription factor in the aorta under physiological conditions in vivo. Inhibition of Sp1- Kcna5 promoter interactions using mithramycin A, a dominant-negative Sp1 mutant, or disruption of the CACCC boxes by mutagenesis inhibited promoter activity. Conversely, expression of exogenous Sp1 augmented promoter activity. Sp1 has known sensitivity to oxidative stress and, consistent with this property, Kcna5 promoter activity was suppressed by hydrogen peroxide-induced oxidative stress. Our results show that Kcna5 promoter activity in vascular smooth muscle is critically dependent on Sp1 regulation via CACCC box motifs and identify mechanisms that potentially influence the expression of KV1.5 channel expression in physiological or pathological conditions.

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8

Paulhus, Kelsey, Lauren Ammerman, and Edward Glasscock. "Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity." International Journal of Molecular Sciences 21, no. 8 (April 17, 2020): 2802. http://dx.doi.org/10.3390/ijms21082802.

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Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype–phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, some patients have EA1 in combination with epilepsy, whereas others have epilepsy alone. KCNA1 mutations can also cause hypomagnesemia and paroxysmal dyskinesia in rare cases. Why KCNA1 variants are associated with such phenotypic heterogeneity in patients is not yet understood. In this review, literature databases (PubMed) and public genetic archives (dbSNP and ClinVar) were mined for known pathogenic or likely pathogenic mutations in KCNA1 to examine whether patterns exist between mutation type and disease manifestation. Analyses of the 47 deleterious KCNA1 mutations that were identified revealed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein. In addition, insights from animal models of KCNA1 channelopathy were considered, as well as the possible influence of genetic modifiers on disease expressivity and severity. Elucidation of the complex relationship between KCNA1 variants and disease will enable better diagnostic risk assessment and more personalized therapeutic strategies for KCNA1 channelopathy.

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9

Ślęczkowska, Milena, Rowida Almomani, Margherita Marchi, Erika Salvi, Bianca T. A. de Greef, Maurice Sopacua, Janneke G. J. Hoeijmakers, et al. "Peripheral Ion Channel Genes Screening in Painful Small Fiber Neuropathy." International Journal of Molecular Sciences 23, no. 22 (November 15, 2022): 14095. http://dx.doi.org/10.3390/ijms232214095.

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Neuropathic pain is a characteristic feature of small fiber neuropathy (SFN), which in 18% of the cases is caused by genetic variants in voltage-gated sodium ion channels. In this study, we assessed the role of fifteen other ion channels in neuropathic pain. Patients with SFN (n = 414) were analyzed for ANO1, ANO3, HCN1, KCNA2, KCNA4, KCNK18, KCNN1, KCNQ3, KCNQ5, KCNS1, TRPA1, TRPM8, TRPV1, TRPV3 and TRPV4 variants by single-molecule molecular inversion probes–next-generation sequencing. These patients did not have genetic variants in SCN3A, SCN7A-SCN11A and SCN1B-SCN4B. In twenty patients (20/414, 4.8%), a potentially pathogenic heterozygous variant was identified in an ion-channel gene (ICG). Variants were present in seven genes, for two patients (0.5%) in ANO3, one (0.2%) in KCNK18, two (0.5%) in KCNQ3, seven (1.7%) in TRPA1, three (0.7%) in TRPM8, three (0.7%) in TRPV1 and two (0.5%) in TRPV3. Variants in the TRP genes were the most frequent (n = 15, 3.6%), partly in patients with high mean maximal pain scores VAS = 9.65 ± 0.7 (n = 4). Patients with ICG variants reported more severe pain compared to patients without such variants (VAS = 9.36 ± 0.72 vs. VAS = 7.47 ± 2.37). This cohort study identified ICG variants in neuropathic pain in SFN, complementing previous findings of ICG variants in diabetic neuropathy. These data show that ICG variants are central in neuropathic pain of different etiologies and provides promising gene candidates for future research.

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10

Platoshyn, Oleksandr, Elena E. Brevnova, Elyssa D. Burg, Ying Yu, Carmelle V. Remillard, and Jason X. J. Yuan. "Acute hypoxia selectively inhibits KCNA5 channels in pulmonary artery smooth muscle cells." American Journal of Physiology-Cell Physiology 290, no. 3 (March 2006): C907—C916. http://dx.doi.org/10.1152/ajpcell.00028.2005.

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Acute hypoxia causes pulmonary vasoconstriction in part by inhibiting voltage-gated K+ (Kv) channel activity in pulmonary artery smooth muscle cells (PASMC). The hypoxia-mediated decrease in Kv currents [ IK(V)] is selective to PASMC; hypoxia has little effect on IK(V) in mesenteric artery smooth muscle cells (MASMC). Functional Kv channels are homo- and/or heterotetramers of pore-forming α-subunits and regulatory β-subunits. KCNA5 is a Kv channel α-subunit that forms functional Kv channels in PASMC and regulates resting membrane potential. We have shown that acute hypoxia selectively inhibits IK(V) through KCNA5 channels in PASMC. Overexpression of the human KCNA5 gene increased IK(V) and caused membrane hyperpolarization in HEK-293, COS-7, and rat MASMC and PASMC. Acute hypoxia did not affect IK(V) in KCNA5-transfected HEK-293 and COS-7 cells. However, overexpression of KCNA5 in PASMC conferred its sensitivity to hypoxia. Reduction of Po2 from 145 to 35 mmHg reduced IK(V) by ∼40% in rat PASMC transfected with human KCNA5 but had no effect on IK(V) in KCNA5-transfected rat MASMC (or HEK and COS cells). These results indicate that KCNA5 is an important Kv channel that regulates resting membrane potential and that acute hypoxia selectively reduces KCNA5 channel activity in PASMC relative to MASMC and other cell types. Because Kv channels (including KCNA5) are ubiquitously expressed in PASMC and MASMC, the observation from this study indicates that a hypoxia-sensitive mechanism essential for inhibiting KCNA5 channel activity is exclusively present in PASMC. The divergent effect of hypoxia on IK(V) in PASMC and MASMC also may be due to different expression levels of KCNA5 channels.

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11

Flecha-Velazquez, Keven, Thomas Fahey, Juan Martínez, Juan Lopez-Taylor, and Miguel Rivera. "KCNA4 Gene Variant is Auxiliary in Endurance Running Performance Level." International Journal of Sports Medicine 40, no. 05 (February 27, 2019): 354–58. http://dx.doi.org/10.1055/a-0824-5394.

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AbstractThe present is an observational study following a genetic epidemiology model using a case-control design. We tested the hypothesis of an association between the prevalence of the genotypic and allelic frequencies distribution of the potassium voltage-gated channel of the shaker related subfamily member 4 gene (KCNA4) rs1323860 (C/T transition) and endurance performance level in Hispanic male marathon runners (MR). The subjects (n=1876) were adult Hispanic male MR. Fast-MR (cases; n=938) were finishers in the top 3rd percentile. Slow MR (controls; n=938) were finishers in the lowest 3rd percentile of their respective age. Genomic DNA was purified from a whole blood sample. Polymerase chain reaction was used to amplify a KCNA4 SNP which consists of a C/T (rs1323860) transition. The observed genotype frequencies, in both Cases and Controls, met Hardy-Weinberg equilibrium (X2, P≥0.05). Genotype and allele frequencies were statistically different (P<0.01) between cases and controls. Odds ratio revealed that the C allele was 1.33 times more likely prevalent in the cases than in the controls (95% CI; 1.17, 1.51; P<0.001). The magnitude of the statistical power for the present study was 0.86. In conclusion, the findings strongly suggest that KCNA4 gene rs1323860 (C/T transition) is auxiliary in the complex phenotype of endurance running performance level in Hispanic male marathon runners.

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Wymore, Randy S., Julie R. Korenberg, Keith D. Kinoshita, Jayashree Aiyar, Christopher Coyne, Xiao-Ning Chen, Carolyn M. Hustad, et al. "Genomic Organization, Nucleotide Sequence, Biophysical Properties, and Localization of the Voltage-Gated K+ Channel Gene KCNA4/Kv1.4 to Mouse Chromosome 2/Human 11p14 and Mapping of KCNC1/Kv3.1 to Mouse 7/Human 11p14.3-p15.2 and KCNA1/Kv1.1 to Human 12p13." Genomics 20, no. 2 (March 1994): 191–202. http://dx.doi.org/10.1006/geno.1994.1153.

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13

Philipson, Louis H., Roger L. Eddy, Thomas B. Shows, and Graeme I. Bell. "Assignment of Human Potassium Channel Gene KCNA4 (Kv1.4, PCN2) to Chromosome 11q13.4 → q14.1." Genomics 15, no. 2 (February 1993): 463–64. http://dx.doi.org/10.1006/geno.1993.1094.

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Padró, Carmen A., Miguel A. Rivera, Tuomo Rankinen, Arthur S. Leon, James S. Skinner, Jack H. Wilmore, D. C. Rao, and Claude Bouchard. "KCNA4 Gene SNP and OV2max Response to Endurance Training." Medicine & Science in Sports & Exercise 36, Supplement (May 2004): S99. http://dx.doi.org/10.1249/00005768-200405001-00468.

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15

Padr??, Carmen A., Miguel A. Rivera, Tuomo Rankinen, Arthur S. Leon, James S. Skinner, Jack H. Wilmore, D. C. Rao, and Claude Bouchard. "KCNA4 Gene SNP and OV2max Response to Endurance Training." Medicine & Science in Sports & Exercise 36, Supplement (May 2004): S99. http://dx.doi.org/10.1097/00005768-200405001-00468.

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16

Simard, Chantale, Benoit Drolet, Ping Yang, Richard B. Kim, and Dan M. Roden. "Polymorphism Screening in the Cardiac K+ Channel Gene KCNA5*." Clinical Pharmacology & Therapeutics 77, no. 3 (March 2005): 138–44. http://dx.doi.org/10.1016/j.clpt.2004.10.008.

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17

Dinoi, Giorgia, Michael Morin, Elena Conte, Hagar Mor Shaked, Maria Antonietta Coppola, Maria Cristina D’Adamo, Orly Elpeleg, et al. "Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia." International Journal of Molecular Sciences 23, no. 15 (July 22, 2022): 8079. http://dx.doi.org/10.3390/ijms23158079.

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Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype–phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies.

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Imbrici, Paola, Elena Conte, Rikard Blunck, Fabrizia Stregapede, Antonella Liantonio, Michele Tosi, Maria Cristina D’Adamo, Annamaria De Luca, Vesna Brankovic, and Ginevra Zanni. "A Novel KCNA2 Variant in a Patient with Non-Progressive Congenital Ataxia and Epilepsy: Functional Characterization and Sensitivity to 4-Aminopyridine." International Journal of Molecular Sciences 22, no. 18 (September 14, 2021): 9913. http://dx.doi.org/10.3390/ijms22189913.

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Kv1.2 channels, encoded by the KCNA2 gene, are localized in the central and peripheral nervous system, where they regulate neuronal excitability. Recently, heterozygous mutations in KCNA2 have been associated with a spectrum of symptoms extending from epileptic encephalopathy, intellectual disability, and cerebellar ataxia. Patients are treated with a combination of antiepileptic drugs and 4-aminopyridine (4-AP) has been recently trialed in specific cases. We identified a novel variant in KCNA2, E236K, in a Serbian proband with non-progressive congenital ataxia and early onset epilepsy, treated with sodium valproate. To ascertain the pathogenicity of E236K mutation and to verify its sensitivity to 4-AP, we transfected HEK 293 cells with Kv1.2 WT or E236K cDNAs and recorded potassium currents through the whole-cell patch-clamp. In silico analysis supported the electrophysiological data. E236K channels showed voltage-dependent activation shifted towards negative potentials and slower kinetics of deactivation and activation compared with Kv1.2 WT. Heteromeric Kv1.2 WT+E236K channels, resembling the condition of the heterozygous patient, confirmed a mixed gain- and loss-of-function (GoF/LoF) biophysical phenotype. 4-AP inhibited both Kv1.2 and E236K channels with similar potency. Homology modeling studies of mutant channels suggested a reduced interaction between the residue K236 in the S2 segment and the gating charges at S4. Overall, the biophysical phenotype of E236K channels correlates with the mild end of the clinical spectrum reported in patients with GoF/LoF defects. The response to 4-AP corroborates existing evidence that KCNA2-disorders could benefit from variant-tailored therapeutic approaches, based on functional studies.

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Burg, Elyssa D., Oleksandr Platoshyn, Igor F. Tsigelny, Beatriz Lozano-Ruiz, Brinda K. Rana, and Jason X. J. Yuan. "Tetramerization domain mutations in KCNA5 affect channel kinetics and cause abnormal trafficking patterns." American Journal of Physiology-Cell Physiology 298, no. 3 (March 2010): C496—C509. http://dx.doi.org/10.1152/ajpcell.00464.2009.

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The activity of voltage-gated K+ (KV) channels plays an important role in regulating pulmonary artery smooth muscle cell (PASMC) contraction, proliferation, and apoptosis. The highly conserved NH2-terminal tetramerization domain (T1) of KV channels is important for proper channel assembly, association with regulatory KV β-subunits, and localization of the channel to the plasma membrane. We recently reported two nonsynonymous mutations (G182R and E211D) in the KCNA5 gene of patients with idiopathic pulmonary arterial hypertension, which localize to the T1 domain of KCNA5. To study the electrophysiological properties and expression patterns of the mutants compared with the wild-type (WT) channel in vitro, we transfected HEK-293 cells with WT KCNA5, G182R, E211D, or the double mutant G182R/E211D channel. The mutants form functional channels; however, whole cell current kinetic differences between WT and mutant channels exist. Steady-state inactivation curves of the G182R and G182R/E211D channels reveal accelerated inactivation; the mutant channels inactivated at more hyperpolarized potentials compared with the WT channel. Channel protein expression was also decreased by the mutations. Compared with the WT channel, which was present in its mature glycosylated form, the mutant channels are present in greater proportion in their immature form in HEK-293 cells. Furthermore, G182R protein level is greatly reduced in COS-1 cells compared with WT. Immunostaining data support the hypothesis that, while WT protein localizes to the plasma membrane, mutant protein is mainly retained in intracellular packets. Overall, these data support a role for the T1 domain in channel kinetics as well as in KCNA5 channel subcellular localization.

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Imbrici, Paola, Andrea Accogli, Rikard Blunck, Concetta Altamura, Michele Iacomino, Maria Cristina D’Adamo, Anna Allegri, et al. "Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in KCNA1 Impairing the Voltage Sensitivity of Kv1.1 Channel." Biomedicines 9, no. 1 (January 14, 2021): 75. http://dx.doi.org/10.3390/biomedicines9010075.

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The KCNA1 gene encodes the α subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2–S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation.

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Gittelman, Joshua X., and Bruce L. Tempel. "Kv1.1-Containing Channels Are Critical for Temporal Precision During Spike Initiation." Journal of Neurophysiology 96, no. 3 (September 2006): 1203–14. http://dx.doi.org/10.1152/jn.00092.2005.

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Low threshold, voltage-gated potassium currents ( Ikl) are widely expressed in auditory neurons that can fire temporally precise action potentials (APs). In the medial nucleus of the trapezoid body (MNTB), channels containing the Kv1.1 subunit (encoded by the Kcna1 gene) underlie Ikl. Using pharmacology, genetics and whole cell patch-clamp recordings in mouse brain slices, we tested the role of Ikl in limiting AP latency-variability (jitter) in response to trains of single inputs at moderate to high stimulation rates. With dendrotoxin-K (DTX-K, a selective blocker of Kv1.1-containing channels), we blocked Ikl maximally (≈80% with 100 nM DTX-K) or partially (≈50% with 1-h incubation in 3 nM DTX-K). Ikl was similar in 3 nM DTX-K–treated cells and cells from Kcna1−/− mice, allowing a comparison of these two different methods of Ikl reduction. In response to current injection, Ikl reduction increased the temporal window for AP initiation and increased jitter in response to the smallest currents that were able to drive APs. While 100 nM DTX-K caused the largest increases, latency and jitter in Kcna1 −/ − cells and in 3 nM DTX-K–treated cells were similar to each other but increased compared with +/+. The near-phenocopy of the Kcna1−/− cells with 3 nM DTX-K shows that acute blockade of a subset of the Kv1.1-containing channels is functionally similar to the chronic elimination of all Kv1.1 subunits. During rapid stimulation (100–500 Hz), Ikl reduction increased jitter in response to both large and small inputs. These data show that Ikl is critical for maintaining AP temporal precision at physiologically relevant firing rates.

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D’Adamo, Maria Cristina, Antonella Liantonio, Jean-Francois Rolland, Mauro Pessia, and Paola Imbrici. "Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches." International Journal of Molecular Sciences 21, no. 8 (April 22, 2020): 2935. http://dx.doi.org/10.3390/ijms21082935.

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Kv1.1 belongs to the Shaker subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. KCNA1 is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal dominant disorder characterized by ataxia and myokymia and for which different and variable phenotypes have now been reported. The iterative characterization of channel defects at the molecular, network, and organismal levels contributed to elucidating the functional consequences of KCNA1 mutations and to demonstrate that ataxic attacks and neuromyotonia result from cerebellum and motor nerve alterations. Dysfunctions of the Kv1.1 channel have been also associated with epilepsy and kcna1 knock-out mouse is considered a model of sudden unexpected death in epilepsy. The tissue-specific association of Kv1.1 with other Kv1 members, auxiliary and interacting subunits amplifies Kv1.1 physiological roles and expands the pathogenesis of Kv1.1-associated diseases. In line with the current knowledge, Kv1.1 has been proposed as a novel and promising target for the treatment of brain disorders characterized by hyperexcitability, in the attempt to overcome limited response and side effects of available therapies. This review recounts past and current studies clarifying the roles of Kv1.1 in and beyond the nervous system and its contribution to EA1 and seizure susceptibility as well as its wide pharmacological potential.

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Remillard, Carmelle V., Donna D. Tigno, Oleksandr Platoshyn, Elyssa D. Burg, Elena E. Brevnova, Diane Conger, Ann Nicholson, et al. "Function of Kv1.5 channels and genetic variations ofKCNA5in patients with idiopathic pulmonary arterial hypertension." American Journal of Physiology-Cell Physiology 292, no. 5 (May 2007): C1837—C1853. http://dx.doi.org/10.1152/ajpcell.00405.2006.

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The pore-forming α-subunit, Kv1.5, forms functional voltage-gated K+(Kv) channels in human pulmonary artery smooth muscle cells (PASMC) and plays an important role in regulating membrane potential, vascular tone, and PASMC proliferation and apoptosis. Inhibited Kv channel expression and function have been implicated in PASMC from patients with idiopathic pulmonary arterial hypertension (IPAH). Here, we report that overexpression of the Kv1.5 channel gene ( KCNA5) in human PASMC and other cell lines produced a 15-pS single channel current and a large whole cell current that was sensitive to 4-aminopyridine. Extracellular application of nicotine, bepridil, correolide, and endothelin-1 (ET-1) all significantly and reversibly reduced the Kv1.5 currents, while nicotine and bepridil also accelerated the inactivation kinetics of the currents. Furthermore, we sequenced KCNA5 from IPAH patients and identified 17 single-nucleotide polymorphisms (SNPs); 7 are novel SNPs. There are 12 SNPs in the upstream 5′ region, 2 of which may alter transcription factor binding sites in the promoter, 2 nonsynonymous SNPs in the coding region, 2 SNPs in the 3′-untranslated region, and 1 SNP in the 3′-flanking region. Two SNPs may correlate with the nitric oxide-mediated decrease in pulmonary arterial pressure. Allele frequency of two other SNPs in patients with a history of fenfluramine and phentermine use was significantly different from patients who have never taken the anorexigens. These results suggest that 1) Kv1.5 channels are modulated by various agonists (e.g., nicotine and ET-1); 2) novel SNPs in KCNA5 are present in IPAH patients; and 3) SNPs in the promoter and translated regions of KCNA5 may underlie the altered expression and/or function of Kv1.5 channels in PASMC from IPAH patients.

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Nielsen, Nathalie H., Bo G. Winkel, Jørgen K. Kanters, Nicole Schmitt, Jacob Hofman-Bang, Henrik S. Jensen, Bo H. Bentzen, et al. "Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients." Biochemical and Biophysical Research Communications 354, no. 3 (March 2007): 776–82. http://dx.doi.org/10.1016/j.bbrc.2007.01.048.

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Lutz, Brianna Marie, Alex Bekker, and Yuan-Xiang Tao. "Noncoding RNAs." Anesthesiology 121, no. 2 (August 1, 2014): 409–17. http://dx.doi.org/10.1097/aln.0000000000000265.

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Abstract Chronic pain, a common clinical symptom, is often treated inadequately or ineffectively in part due to the incomplete understanding of molecular mechanisms that initiate and maintain this disorder. Newly identified noncoding RNAs govern gene expression. Recent studies have shown that peripheral noxious stimuli drive expressional changes in noncoding RNAs and that these changes are associated with pain hypersensitivity under chronic pain conditions. This review first presents current evidence for the peripheral inflammation/nerve injury–induced change in the expression of two types of noncoding RNAs, microRNAs, and Kcna2 antisense RNA, in pain-related regions, particularly in the dorsal root ganglion. The authors then discuss how peripheral noxious stimuli induce such changes. The authors finally explore potential mechanisms of how expressional changes in dorsal root ganglion microRNAs and Kcna2 antisense RNA contribute to the development and maintenance of chronic pain. An understanding of these mechanisms may propose novel therapeutic strategies for preventing and/or treating chronic pain.

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Hoegg, Simone, and Axel Meyer. "Phylogenomic analyses of KCNA gene clusters in vertebrates: why do gene clusters stay intact?" BMC Evolutionary Biology 7, no. 1 (2007): 139. http://dx.doi.org/10.1186/1471-2148-7-139.

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Xiao, Sophie, Lin Li, Deying Yang, Huiyuan Zhang, Yulun Huang, Wan-Yee Teo, Akash Patel, Yuchen Du, and Xiao-Nan Li. "DDDR-35. TARGETING GBM INVASION BY INHIBITING KCNA1 WITH 4-AMINOPYRIDINE: AN FDA APPROVED DRUG THAT EASILY PASS THROUGH THE BBB." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii106—vii107. http://dx.doi.org/10.1093/neuonc/noac209.400.

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Abstract Diffuse invasion is a hall mark of glioblastoma (GB) and one of the primary causes of poor clinical outcomes in GBM patients. Tumor cells migrate deep into the normal brain tissues are frequently protected by the BBB, making them particularly difficult to treat. New therapeutic targets are needed. Our previous studies using spatially dissected and functionally validated matching pairs of invasive and tumor core GBM cells identified KCNA1 as a shared gene that is selectively over-expressed in the invasive GBM cells in 6 patient derived orthotopic xenograft (PDOX) mouse models of pediatric GBM (Huang YL et al, Adv Science 2021). A subsequent analysis of adult GBM RNAseq data from IVY Atlas revealed a significantly elevated expression of KCNA1 (4.9 fold) in the invasive edges of patient GBM tumors. It is also one of the 11 core molecules identified in GEO and TCGA databases through an integrated bioinformatic analysis (Yang J, Front Onc 2021). To determine the anti-invasive activities of targeting KCNA1, we treated three highly invasive adult GBM PDOX models with 4-aminopyridine (4-AP), an old lipid soluble drug that easily penetrate the BBB, at 5 mg/kg, i.p., 5 days/week for 8 weeks acing alone or in combination with fractionated radiation (at 2 Gy/day x days). As single agent, 4-AP significantly extended median animal survival times in 1/3 GBM models (69 to 77 days, P = 0.033). Combination with XRT did not significantly improve the animal survival times in the three models. Systematic analysis of GBM invasion in mouse brains of the 3 PDOX models before, during and after 4-AP treatment revealed remarkable inhibition of tumor invasion. Our data highlighted the role of KCNA1 in promoting GBM invasion and support the fine tuning of 4-AP dose, schedule, and length of treatment to serve as a novel component of anti-GBM invasion therapies.

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Yin, Xiao-Meng, Jing-Han Lin, Li Cao, Tong-Mei Zhang, Sheng Zeng, Kai-Lin Zhang, Wo-Tu Tian, et al. "Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene." Human Molecular Genetics 27, no. 4 (December 27, 2017): 625–37. http://dx.doi.org/10.1093/hmg/ddx430.

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Yin, Xiao-Meng, Jing-Han Lin, Li Cao, Tong-Mei Zhang, Sheng Zeng, Kai-Lin Zhang, Wo-Tu Tian, et al. "Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene." Human Molecular Genetics 27, no. 4 (January 16, 2018): 757–58. http://dx.doi.org/10.1093/hmg/ddy025.

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Wenzel, H. Jürgen, Helene Vacher, Eliana Clark, James S. Trimmer, Angela L. Lee, Robert M. Sapolsky, Bruce L. Tempel, and Philip A. Schwartzkroin. "Structural Consequences of Kcna1 Gene Deletion and Transfer in the Mouse Hippocampus." Epilepsia 48, no. 11 (November 2007): 2023–46. http://dx.doi.org/10.1111/j.1528-1167.2007.01189.x.

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31

Huang, Yulun, Lin Qi, Mari Kogiso, Yuchen Du, Frank Braun, Huiyuan Zhang, Lei Huang, et al. "PDTM-17. MiR-126, miR-369-5p AND miR-487b DRIVE PEDIATRIC GLIOBLASTOMA INVASION VIA KCNA1." Neuro-Oncology 21, Supplement_6 (November 2019): vi190—vi191. http://dx.doi.org/10.1093/neuonc/noz175.793.

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Abstract Diffuse invasion is one of the key features that make GBM particularly difficult to treat. We hypothesize that direct comparison of matched invasive (GBMINV) and tumor core GBM cells (GBMTC) would facilitate the discovery of drivers of pediatric GBM (pGBM) invasion. However, GBMINV cells are extremely difficult to obtain from normal brain tissues because aggressive surgical resection of normal tissue carries the risk of serious neurological deficits. Most past and current studies on GBM invasion were and are forced to utilize the resected primary tumor masses. To overcome this barrier, we utilized a panel of 6 pediatric patient tumor-derived orthotopic xenograft (PDOX) mouse models to isolate matching pairs of GBMTC cells and GBMINV cells and confirmed a significantly elevated invasive capacity in GBMINV cells both in vitro and in vivo. Global profiling of 768 human microRNA using a real-time PCR-based Taqman system identified 23 microRNAs were upregulated in the GBMINV cells in at least 4 of the 6 pGBM models as compared with the matching GBMTC cells. We subsequently showed that silencing the top three miRNAINV, miR-126, miR-369-5p, and miR-487b, suppressed tumor cell migration in vitro (both as neurospheres and monolayer cultures) without affecting cell proliferation, and blocked pGBM invasion in mouse brains. Integrated analysis of the mRNA profiling of the same set of GBMTC and GBMINV cells revealed the affected signaling pathways and identified KCNA1 as the sole common computational target gene of the three miRNAINV. Treatment of three pairs of GBMTC and GBMINV cells with two KCNA1 inhibitors, ADWX1 and Agitoxin 2, caused significant suppression of pGBM cell migration in vitro. In conclusion, this study revealed an intrinsically elevated invasive phenotype in GBMINV cells, identified miR-126, -369-5p, and -487b as novel drivers of pGBM invasion, and characterized KCNA1 as a potential therapeutic target for arresting pGBM invasion.

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32

Camelo, Clara Gontijo, André Macedo Serafim Silva, Cristiane Araújo Martins Moreno, Ciro Matsui-Júnior, Carlos Otto Heise, José Luiz Pedroso, and Edmar Zanoteli. "Facial myokymia in inherited peripheral nerve hyperexcitability syndrome." Practical Neurology 20, no. 3 (March 17, 2020): 253–55. http://dx.doi.org/10.1136/practneurol-2019-002462.

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Peripheral nerve hyperexcitability syndrome comprises a heterogeneous group of diseases, clinically characterised by myokymia, fasciculation, muscle cramps and stiffness. The causes are either immune mediated or non-immune mediated. Non-immune-mediated forms are mostly genetic, relating to two main genes: KCNQ2 and KCNA1. Patients with KCNQ2 gene mutations typically present with epileptic encephalopathy, benign familial neonatal seizures and myokymia, though occasionally with purely peripheral nerve hyperexcitability. We report a woman with marked facial myokymia and distal upper limb contractures whose mother also had subtle facial myokymia; both had the c.G620A (p.R207Q) variant in the KCNQ2 gene. Patients with familial myokymia and peripheral nerve hyperexcitability syndrome should be investigated for KCNQ2 variants. This autosomal dominant condition may respond to antiepileptic medications acting at potassium channels.

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Folander, Kimberly, James Douglass, and Richard Swanson. "Confirmation of the Assignment of the Gene Encoding Kv1.3, a Voltage-Gated Potassium Channel (KCNA3) to the Proximal Short Arm of Human Chromosome 1." Genomics 23, no. 1 (September 1994): 295–96. http://dx.doi.org/10.1006/geno.1994.1500.

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34

Weng, Jingyin, and Nicole Salazar. "DNA Methylation Analysis Identifies Patterns in Progressive Glioma Grades to Predict Patient Survival." International Journal of Molecular Sciences 22, no. 3 (January 20, 2021): 1020. http://dx.doi.org/10.3390/ijms22031020.

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DNA methylation is an epigenetic change to the genome that impacts gene activities without modification to the DNA sequence. Alteration in the methylation pattern is a naturally occurring event throughout the human life cycle which may result in the development of diseases such as cancer. In this study, we analyzed methylation data from The Cancer Genome Atlas, under the Lower-Grade Glioma (LGG) and Glioblastoma Multiforme (GBM) projects, to identify methylation markers that exhibit unique changes in DNA methylation pattern along with tumor grade progression, to predict patient survival. We found ten glioma grade-associated Cytosine-phosphate-Guanine (CpG) sites that targeted four genes (SMOC1, KCNA4, SLC25A21, and UPP1) and the methylation pattern is strongly associated with glioma specific molecular alterations, primarily isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion. The ten CpG sites collectively distinguished a cohort of diffuse glioma patients with remarkably poor survival probability. Our study highlights genes (KCNA4 and SLC25A21) that were not previously associated with gliomas to have contributed to the poorer patient outcome. These CpG sites can aid glioma tumor progression monitoring and serve as prognostic markers to identify patients diagnosed with less aggressive and malignant gliomas that exhibit similar survival probability to GBM patients.

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Ai, Jiao, Mao Liu, Zhuang Shuai, Kai Tang, Jiankang Zheng, Jinxi Yang, and Lihan Peng. "KCNA5 gene variation is not associated with the pulmonary hypertension in systemic sclerosis patients." Journal of Xiangya Medicine 4 (August 2019): 32. http://dx.doi.org/10.21037/jxym.2019.07.04.

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Flecha-Velazquez, Keven, Thomas D. Fahey, Juan L. Martinez-Barreda, Juan R. Lopez-Taylor, and Miguel A. Rivera. "KCNA4 Gene Variant is Auxiliary in the Complex Phenotype of Endurance Running Performance Level." Medicine & Science in Sports & Exercise 51, Supplement (June 2019): 576. http://dx.doi.org/10.1249/01.mss.0000562232.34471.79.

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37

Abdul Sani, Nur Fathiah Abdul, Ahmad Imran Zaydi Amir Amir Hamzah, Zulzikry Hafiz Abu Abu Bakar, Yasmin Anum Mohd Mohd Yusof, Suzana Makpol, Wan Zurinah Wan Wan Ngah, and Hanafi Ahmad Damanhuri. "Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia." Cells 10, no. 7 (June 27, 2021): 1611. http://dx.doi.org/10.3390/cells10071611.

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The mechanism of cognitive aging at the molecular level is complex and not well understood. Growing evidence suggests that cognitive differences might also be caused by ethnicity. Thus, this study aims to determine the gene expression changes associated with age-related cognitive decline among Malay adults in Malaysia. A cross-sectional study was conducted on 160 healthy Malay subjects, aged between 28 and 79, and recruited around Selangor and Klang Valley, Malaysia. Gene expression analysis was performed using a HumanHT-12v4.0 Expression BeadChip microarray kit. The top 20 differentially expressed genes at p < 0.05 and fold change (FC) = 1.2 showed that PAFAH1B3, HIST1H1E, KCNA3, TM7SF2, RGS1, and TGFBRAP1 were regulated with increased age. The gene set analysis suggests that the Malay adult’s susceptibility to developing age-related cognitive decline might be due to the changes in gene expression patterns associated with inflammation, signal transduction, and metabolic pathway in the genetic network. It may, perhaps, have important implications for finding a biomarker for cognitive decline and offer molecular targets to achieve successful aging, mainly in the Malay population in Malaysia.

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38

Gardiner, A. R., R. Mannikko, S. Schorge, H. Houlden, and M. Hanna. "P46 Functional investigation of a novel mutation causing a new phenotype for the KCNA1 gene." Neuromuscular Disorders 24 (March 2014): S19. http://dx.doi.org/10.1016/s0960-8966(14)70062-8.

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39

Poujois, A., J. Ch Antoine, A. Combes, and R. L. Touraine. "Chronic neuromyotonia as a phenotypic variation associated with a new mutation in the KCNA1 gene." Journal of Neurology 253, no. 7 (March 6, 2006): 957–59. http://dx.doi.org/10.1007/s00415-006-0134-y.

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40

Yost, C. Spencer, Irene Oh, Edmond I. Eger, and James M. Sonner. "Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity." Behavioural Brain Research 193, no. 2 (November 2008): 192–96. http://dx.doi.org/10.1016/j.bbr.2008.05.010.

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41

Ison, James R., Paul D. Allen, Bruce L. Tempel, and Helen M. Brew. "Sound Localization in Preweanling Mice Was More Severely Affected by Deleting the Kcna1 Gene Compared to Deleting Kcna2, and a Curious Inverted-U Course of Development That Appeared to Exceed Adult Performance Was Observed in All Groups." Journal of the Association for Research in Otolaryngology 20, no. 6 (August 13, 2019): 565–77. http://dx.doi.org/10.1007/s10162-019-00731-5.

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42

Browne, David L., Stephen T. Gancher, John G. Nutt, Ewout R. P. Brunt, Eric A. Smith, Patricia Kramer, and Michael Litt. "Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1." Nature Genetics 8, no. 2 (October 1994): 136–40. http://dx.doi.org/10.1038/ng1094-136.

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43

Bossini-Castillo, Lara, Carmen P. Simeon, Lorenzo Beretta, Jasper Broen, Madelon C. Vonk, José Callejas, Patricia Carreira, et al. "KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor." Arthritis Research & Therapy 14, no. 6 (2012): R273. http://dx.doi.org/10.1186/ar4124.

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44

Eunson, L. H., R. Rea, S. M. Zuberi, S. Youroukos, C. P. Panayiotopoulos, R. Liguori, P. Avoni, et al. "Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability." Annals of Neurology 48, no. 4 (October 2000): 647–56. http://dx.doi.org/10.1002/1531-8249(200010)48:4<647::aid-ana12>3.0.co;2-q.

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45

Jiao, Yu-rui, Wei Wang, Peng-cheng Lei, Hui-ping Jia, Jie Dong, Yun-qian Gou, Cheng-long Chen, Jie Cao, Ya-feng Wang, and Yi-kun Zhu. "5-HTT, BMPR2, EDN1, ENG, KCNA5 gene polymorphisms and susceptibility to pulmonary arterial hypertension: A meta-analysis." Gene 680 (January 2019): 34–42. http://dx.doi.org/10.1016/j.gene.2018.09.020.

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46

Colasante, Gaia, Yichen Qiu, Luca Massimino, Claudia Di Berardino, Jonathan H. Cornford, Albert Snowball, Mikail Weston, et al. "In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy." Brain 143, no. 3 (March 1, 2020): 891–905. http://dx.doi.org/10.1093/brain/awaa045.

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Abstract Epilepsy is a major health burden, calling for new mechanistic insights and therapies. CRISPR-mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex vivo. Its translational potential for treating non-genetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR, because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can effectively treat acquired focal epilepsy, focusing on ion channels because their manipulation is known be effective in changing network hyperactivity and hypersynchronziation. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video-EEG telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic-clonic seizures in a model of temporal lobe epilepsy, and rescued cognitive impairment and transcriptomic alterations associated with chronic epilepsy. The focal treatment minimizes concerns about off-target effects in other organs and brain areas. This study provides the proof-of-principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability.

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Bhattacharjee, Shakya, Anu Deenadayalu, and Vijayashankar Paramanandam. "Interictal Headache, Pseudodystonia, and Persistent Ataxia in Episodic Ataxia Type 1 Due to a Novel KCNA1 Gene Mutation." Movement Disorders Clinical Practice 9, no. 2 (December 6, 2021): 272–74. http://dx.doi.org/10.1002/mdc3.13381.

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48

Ryland, K. E., L. K. Svoboda, E. D. Vesely, J. C. McIntyre, L. Zhang, J. R. Martens, and E. R. Lawlor. "Polycomb-dependent repression of the potassium channel-encoding gene KCNA5 promotes cancer cell survival under conditions of stress." Oncogene 34, no. 35 (December 1, 2014): 4591–600. http://dx.doi.org/10.1038/onc.2014.384.

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49

Rees, M., F. Elmslie, W. Whitehouse, A. Sundqvist, and M. Gardiner. "Analysis of a Human Brain Voltage-Gated Potassium Channel Gene, KCNA6 (HBK2), in Patients with Juvenile Myoclonic Epilepsy." Neuropediatrics 26, no. 06 (December 1995): 333–34. http://dx.doi.org/10.1055/s-2007-979787.

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Imbrici, P., F. Gualandi, M. D’Adamo, P. Cudia, D. De Grandis, A. Ferlini, and M. Pessia. "G.P.18.09 Functional characterisation of a novel mutation causing episodic ataxia type 1 occurring in the KCNA1 gene." Neuromuscular Disorders 17, no. 9-10 (October 2007): 892–93. http://dx.doi.org/10.1016/j.nmd.2007.06.436.

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