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https://www.readbyqxmd.com/read/29760947/incorporating-epilepsy-genetics-into-clinical-practice-a-360%C3%A2-evaluation
#1
Stephanie Oates, Shan Tang, Richard Rosch, Rosalie Lear, Elaine F Hughes, Ruth E Williams, Line H G Larsen, Qin Hao, Hans Atli Dahl, Rikke S Møller, Deb K Pal
We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29748663/direct-neurotransmitter-activation-of-voltage-gated-potassium-channels
#2
Rían W Manville, Maria Papanikolaou, Geoffrey W Abbott
Voltage-gated potassium channels KCNQ2-5 generate the M-current, which controls neuronal excitability. KCNQ2-5 subunits each harbor a high-affinity anticonvulsant drug-binding pocket containing an essential tryptophan (W265 in human KCNQ3) conserved for >500 million years, yet lacking a known physiological function. Here, phylogenetic analysis, electrostatic potential mapping, in silico docking, electrophysiology, and radioligand binding assays reveal that the anticonvulsant binding pocket evolved to accommodate endogenous neurotransmitters including γ-aminobutyric acid (GABA), which directly activates KCNQ5 and KCNQ3 via W265...
May 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29687029/de-novo-kcnq2-mutation-in-one-case-of-epilepsy-of-infancy-with-migrating-focal-seizures-that-evolved-to-infantile-spasms
#3
Haolin Duan, Jing Peng, Miriam Kessi, Fei Yin
Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare type of early-onset epileptic encephalopathy that is characterized by refractory migratory multifocal seizures that migrate between hemispheres. Its etiology is not well known although it is postulated to occur due to channelopathy. The authors report the first case of EIMFS due to a de novo heterozygous mutation in exon 4(c.881C>T missense mutation, p.Ala294Val, NM_172107.2) in KCNQ2 gene which later evolved into infantile spasms. However, it is the second case of EIMFS with KCNQ2 mutation...
2018: Child Neurology Open
https://www.readbyqxmd.com/read/29614566/-spectrum-of-mutations-in-benign-familial-neonatal-infantile-epilepsy
#4
Q Zeng, Y H Zhang, X L Yang, L H Pu, J Zhang, A J Liu, Z X Yang, X Y Liu, X R Wu
Objective: To investigate the spectrum of mutations in families with benign familial neonatal-infantile epilepsy (BFNIE) . Methods: Clinical data and peripheral blood DNA samples of all BFNIE probands and their family members were collected from Peking University First Hospital between December 2012 and April 2016. Clinical phenotypes of affected members were analyzed. Genomic DNA was extracted from peripheral blood samples with standard protoco1. Mutations in PRRT2 were screened using Sanger sequencing. For families that PRRT2 mutations were not detected by Sanger sequencing, candidate gene mutations were further screened by next-generation sequencing for epilepsy...
April 2, 2018: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
https://www.readbyqxmd.com/read/29593528/a-statistical-thermodynamic-model-for-ligands-interacting-with-ion-channels-theoretical-model-and-experimental-validation-of-the-kcnq2-channel
#5
Fang Bai, Xiaoping Pi, Ping Li, Pingzheng Zhou, Huaiyu Yang, Xicheng Wang, Min Li, Zhaobing Gao, Hualiang Jiang
Ion channels are important therapeutic targets, and their pharmacology is becoming increasingly important. However, knowledge of the mechanism of interaction of the activators and ion channels is still limited due to the complexity of the mechanisms. A statistical thermodynamic model has been developed in this study to characterize the cooperative binding of activators to ion channels. By fitting experimental concentration-response data, the model gives eight parameters for revealing the mechanism of an activator potentiating an ion channel, i...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29588993/common-terms-for-rare-epilepsies-synonyms-associated-terms-and-links-to-structured-vocabularies
#6
Zachary M Grinspan, Niu Tian, Elissa G Yozawitz, Patricia E McGoldrick, Steven M Wolf, Tiffani L McDonough, Aaron Nelson, Baria Hafeez, Stephen B Johnson, Dale C Hesdorffer
Identifying individuals with rare epilepsy syndromes in electronic data sources is difficult, in part because of missing codes in the International Classification of Diseases (ICD) system. Our objectives were the following: (1) to describe the representation of rare epilepsies in other medical vocabularies, to identify gaps; and (2) to compile synonyms and associated terms for rare epilepsies, to facilitate text and natural language processing tools for cohort identification and population-based surveillance...
March 2018: Epilepsia Open
https://www.readbyqxmd.com/read/29588952/gene-panel-analysis-for-nonsyndromic-cryptogenic-neonatal-infantile-epileptic-encephalopathy
#7
Cheuk-Wing Fung, Anna Ka-Yee Kwong, Virginia Chun-Nei Wong
Objective: Epileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high-throughput next-generation sequencing (NGS) was used to investigate the genetic causes of non-syndromic cryptogenic neonatal/infantile EE (NIEE)...
June 2017: Epilepsia Open
https://www.readbyqxmd.com/read/29579054/the-expression-and-function-of-kcnq-potassium-channels-in-human-chorionic-plate-arteries-from-women-with-normal-pregnancies-and-pre-eclampsia
#8
Xiaohong Wei, Yujiao Zhang, Benlan Yin, Jing Wen, Jun Cheng, Xiaodong Fu
Pre-eclampsia is associated with altered maternal and placental vascular reactivity. Kv7 channels (encoded by KCNQ 1-5 genes) are a potential contributor to the regulation of vascular tone in CPAs (chorionic plate arteries) during normal pregnancy. The aim of this study is to establish the expression profile of KCNQ subunits in CPAs taken from women with preeclampsia or normotensive women and to examine the functional relevance of the Kv7 channels on an altered expression profile of KCNQ subunits. The effects of Kv7 channel modulators on CPAs were investigated by tension measurement...
2018: PloS One
https://www.readbyqxmd.com/read/29561262/the-signaling-lipid-sphingosine-1-phosphate-regulates-mechanical-pain
#9
Rose Z Hill, Benjamin U Hoffman, Takeshi Morita, Stephanie M Campos, Ellen A Lumpkin, Rachel B Brem, Diana M Bautista
Somatosensory neurons mediate responses to diverse mechanical stimuli, from innocuous touch to noxious pain. While recent studies have identified distinct populations of A mechanonociceptors (AMs) that are required for mechanical pain, the molecular underpinnings of mechanonociception remain unknown. Here, we show that the bioactive lipid sphingosine 1-phosphate (S1P) and S1P Receptor 3 (S1PR3) are critical regulators of acute mechanonociception. Genetic or pharmacological ablation of S1PR3, or blockade of S1P production, significantly impaired the behavioral response to noxious mechanical stimuli, with no effect on responses to innocuous touch or thermal stimuli...
March 21, 2018: ELife
https://www.readbyqxmd.com/read/29542386/potassium-channel-gain-of-function-in-epilepsy-an-unresolved-paradox
#10
Zachary Niday, Anastasios V Tzingounis
Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy...
March 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
https://www.readbyqxmd.com/read/29488002/expression-and-regulation-of-m-type-k-channel-in-pc12-cells-and-rat-adrenal-medullary-cells
#11
Keita Harada, Hidetada Matsuoka, Masumi Inoue
M-type K+ channels contribute to the resting membrane potential in the sympathetic ganglion neurons of various animals, whereas their expression in adrenal medullary (AM) cells has been controversial. The present experiment aims to explore the expression of M channels comprising the KCNQ2 subunit in the rat AM cell and its immortalized cell line PC12 cells at the protein level and how its expression in PC12 cells is regulated. The KCNQ2 isoform was recognized in homogenates of PC12 cells but not the rat adrenal medullae by immunoblotting and KCNQ2-like immunoreactivity (IR) was detected in PC12 cells but not in rat AM cells...
June 2018: Cell and Tissue Research
https://www.readbyqxmd.com/read/29463698/structural-basis-and-energy-landscape-for-the-ca-2-gating-and-calmodulation-of-the-kv7-2-k-channel
#12
Ganeko Bernardo-Seisdedos, Eider Nuñez, Carolina Gomis-Perez, Covadonga Malo, Álvaro Villarroel, Oscar Millet
The Kv7.2 (KCNQ2) channel is the principal molecular component of the slow voltage-gated, noninactivating K+ M-current, a key controller of neuronal excitability. To investigate the calmodulin (CaM)-mediated Ca2+ gating of the channel, we used NMR spectroscopy to structurally and dynamically describe the association of helices h A and h B of Kv7.2 with CaM, as a function of Ca2+ concentration. The structures of the CaM/Kv7.2-hAB complex at two different calcification states are reported here. In the presence of a basal cytosolic Ca2+ concentration (10-100 nM), only the N-lobe of CaM is Ca2+ -loaded and the complex (representative of the open channel) exhibits collective dynamics on the millisecond time scale toward a low-populated excited state (1...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29455050/targeted-gene-panel-and-genotype-phenotype-correlation-in-children-with-developmental-and-epileptic-encephalopathy
#13
Ara Ko, Song Ee Youn, Se Hee Kim, Joon Soo Lee, Sangwoo Kim, Jong Rak Choi, Heung Dong Kim, Seung-Tae Lee, Hoon-Chul Kang
OBJECTIVE: We performed targeted gene-panel sequencing for children with developmental and epileptic encephalopathy (DEE) and evaluated the clinical implications of genotype-phenotype correlations. METHODS: We assessed 278 children with DEE using a customized gene panel that included 172 genes, and extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype. RESULTS: In 103 (37.1%) of the 278 patients with DEE, 35 different disease-causing monogenic mutations were identified...
March 2018: Epilepsy Research
https://www.readbyqxmd.com/read/29426806/neonatal-epilepsies-clinical-management
#14
REVIEW
Marie-Coralie Cornet, Tristan T Sands, Maria Roberta Cilio
Whereas the majority of seizures in neonates are related to acute brain injury, a substantial minority are the first symptom of a neonatal-onset epilepsy, often linked to a pathogenic genetic variant. This defect may disrupt cortical development (e.g., lissencephaly, focal cortical dysplasia), lead to metabolic changes (e.g., pyridoxine-dependent epilepsy, sulfite oxidase deficiency) or lead to cortical dysfunction without metabolic or macroscopic structural changes (e.g., channelopathies, STXBP1). Historically, studies on treatment response and long-term consequences of neonatal seizures have lumped all etiologies together...
January 31, 2018: Seminars in Fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/29390993/efficient-strategy-for-the-molecular-diagnosis-of-intractable-early-onset-epilepsy-using-targeted-gene-sequencing
#15
John Hoon Rim, Se Hee Kim, In Sik Hwang, Soon Sung Kwon, Jieun Kim, Hyun Woo Kim, Min Jung Cho, Ara Ko, Song Ee Youn, Jihun Kim, Young Mock Lee, Hee Jung Chung, Joon Soo Lee, Heung Dong Kim, Jong Rak Choi, Seung-Tae Lee, Hoon-Chul Kang
BACKGROUND: We intended to evaluate diagnostic utility of a targeted gene sequencing by using next generation sequencing (NGS) panel in patients with intractable early-onset epilepsy (EOE) and find the efficient analytical step for increasing the diagnosis rate. METHODS: We assessed 74 patients with EOE whose seizures started before 3 years of age using a customized NGS panel that included 172 genes. Single nucleotide variants (SNVs) and exonic and chromosomal copy number variations (CNVs) were intensively examined with our customized pipeline and crosschecked with commercial or pre-built software...
February 1, 2018: BMC Medical Genomics
https://www.readbyqxmd.com/read/29383681/kv7-3-compound-heterozygous-variants-in-early-onset-encephalopathy-reveal-additive-contribution-of-c-terminal-residues-to-pip-2-dependent-k-channel-gating
#16
Paolo Ambrosino, Elena Freri, Barbara Castellotti, Maria Virginia Soldovieri, Ilaria Mosca, Laura Manocchio, Cinzia Gellera, Laura Canafoglia, Silvana Franceschetti, Barbara Salis, Nunzio Iraci, Francesco Miceli, Francesca Ragona, Tiziana Granata, Jacopo C DiFrancesco, Maurizio Taglialatela
Over one hundred mutations in the Kv7.2 (KCNQ2) gene encoding for phosphatidylinositol 4,5-bisphosphate (PIP2 )-sensitive voltage-gated K+ channel subunits have been identified in early-onset epilepsies with wide phenotypic variability. By contrast, only few mutations in the closely related Kv7.3 (KCNQ3) gene have been reported, mostly associated with typical benign familial neonatal seizures (BFNS). We herein describe a patient affected by early onset epileptic encephalopathy (EOEE) carrying two Kv7.3 missense mutations (p...
January 30, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29338302/neurotransmitter-pathway-genes-in-cognitive-decline-during-aging-evidence-for-gng4-and-kcnq2-genes
#17
Luke W Bonham, Daniel S Evans, Yongmei Liu, Steven R Cummings, Kristine Yaffe, Jennifer S Yokoyama
BACKGROUND/RATIONALE: Experimental studies support the role of neurotransmitter genes in dementia risk, but human studies utilizing single variants in candidate genes have had limited success. METHODS: We used the gene-based testing program Versatile Gene-based Association Study to assess whether aggregate variation across 6 neurotransmitter pathways influences risk of cognitive decline in 8159 cognitively normal elderly (≥65 years old) adults from 3 community-based cohorts...
May 2018: American Journal of Alzheimer's Disease and Other Dementias
https://www.readbyqxmd.com/read/29314583/novel-mutations-and-phenotypes-of-epilepsy-associated-genes-in-epileptic-encephalopathies
#18
P Zhou, N He, J-W Zhang, Z-J Lin, J Wang, L-M Yan, H Meng, B Tang, B-M Li, X-R Liu, Y-W Shi, Q-X Zhai, Y-H Yi, W-P Liao
Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next-generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty-three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance...
January 4, 2018: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29215089/genetic-analysis-of-benign-familial-epilepsies-in-the-first-year-of-life-in-a-chinese-cohort
#19
Qi Zeng, Xiaoling Yang, Jing Zhang, Aijie Liu, Zhixian Yang, Xiaoyan Liu, Ye Wu, Xiru Wu, Liping Wei, Yuehua Zhang
Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75...
January 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29190809/molecular-diagnosis-of-patients-with-epilepsy-and-developmental-delay-using-a-customized-panel-of-epilepsy-genes
#20
Laura Ortega-Moreno, Beatriz G Giráldez, Victor Soto-Insuga, Rebeca Losada-Del Pozo, María Rodrigo-Moreno, Cristina Alarcón-Morcillo, Gema Sánchez-Martín, Esther Díaz-Gómez, Rosa Guerrero-López, José M Serratosa
Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel)...
2017: PloS One
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