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Wei Yu, Manasa Gowda, Yashsavi Sharad, Surindo A Singh, Federico Sesti
Oxidative modification of the voltage-gated potassium (K(+)) channel KCNB1 promotes apoptosis in the neurons of cortex and hippocampus through a signaling pathway mediated by Src tyrosine kinases. How oxidation of the channel is transduced into Src recruitment and activation, however, was not known. Here we show that the apoptotic signal originates from integrins, which form macromolecular complexes with KCNB1 channels. The initial stimulus is transduced to Fyn and possibly other Src family members by focal adhesion kinase (FAK)...
April 6, 2017: Cell Death & Disease
P Miao, J Peng, C Chen, N Gai, F Yin
Objective: To explore the association between the phenotype and KCNB1 gene mutation. Method: Clinical information including physical features, laboratory and genetic data of one patient of mental retardation with refractory epilepsy from Department of Pediatrics, Xiangya Hospital in January 2016 was analyzed. This patient was discovered to have KCNB1 gene mutations through whole exome sequencing. Relevant information about KCNB1 gene mutation was searched and collected from Pubmed, CNKI, Human Gene Mutation Database(HGMD) and Online Mendelian Inheritance in Man(OMIM)...
February 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Hao-Yuan Wang, Wen Wang, Yan-Wei Liu, Ming-Yang Li, Ting-Yu Liang, Ji-Ye Li, Hui-Min Hu, Yang Lu, Chen Yao, Yong-Yi Ye, Yong-Zhi Wang, Shi-Zhong Zhang
Increasing evidence suggests that ion channel genes play an important role in the progression of gliomas. However, the mechanisms by which ion channel genes influence the progression of glioma are not fully understood. We identified KCNB1 as a novel ion gene, associated with malignant progression and favorable overall survival (OS) and progression-free survival (PFS) in glioma patients from three datasets (CGGA, GSE16011 and REMBRANDT). Moreover, we characterized a novel function of autophagy induction accompanied by increased apoptosis and reduced proliferation and invasion of glioma cells for KCNB1...
December 2017: Scientific Reports
Xénia Latypova, Naomichi Matsumoto, Cécile Vinceslas-Muller, Stéphane Bézieau, Bertrand Isidor, Noriko Miyake
Potassium voltage-gated channel subfamily B member 1 (KCNB1) encodes Kv2.1 potassium channel of crucial role in hippocampal neuron excitation homeostasis. KCNB1 mutations are known to cause early-onset infantile epilepsy. To date, 10 KCNB1 mutations have been described in 11 patients. Using whole-exome sequencing, we identified a novel de novo missense (c.1132G>C, p.V378L) KCNB1 mutation in a patient with global developmental delay, intellectual disability, severe speech impairment, but no episode of epilepsy until the lastly examined age of 6 years old...
December 8, 2016: Journal of Human Genetics
Wei Yu, Randika Parakramaweera, Shavonne Teng, Manasa Gowda, Yashsavi Sharad, Smita Thakker-Varia, Janet Alder, Federico Sesti
The delayed rectifier potassium (K(+)) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress...
October 26, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Hongyuan Shen, Elke Bocksteins, Igor Kondrychyn, Dirk Snyders, Vladimir Korzh
The brain ventricular system is essential for neurogenesis and brain homeostasis. Its neuroepithelial lining effects these functions, but the underlying molecular pathways remain to be understood. We found that the potassium channels expressed in neuroepithelial cells determine the formation of the ventricular system. The phenotype of a novel zebrafish mutant characterized by denudation of neuroepithelial lining of the ventricular system and hydrocephalus is mechanistically linked to Kcng4b, a homologue of the 'silent' voltage-gated potassium channel α-subunit Kv6...
November 15, 2016: Development
Hao-Yuan Wang, Ji-Ye Li, Xiu Liu, Xiao-Yan Yan, Wen Wang, Fan Wu, Ting-Yu Liang, Fan Yang, Hui-Min Hu, Heng-Xu Mao, Yan-Wei Liu, Shi-Zhong Zhang
Increasing evidence suggests that ion channels not only regulate electric signaling in excitable cells but also play important roles in the development of brain tumor. However, the roles of ion channels in glioma remain controversial. In the present study, we systematically analyzed the expression patterns of ion channel genes in a cohort of Chinese patients with glioma using RNAseq expression profiling. First, a molecular signature comprising three ion channel genes (KCNN4, KCNB1 and KCNJ10) was identified using Univariate Cox regression and two-tailed student's t test conducted in overall survival (OS) and gene expression...
November 15, 2016: Oncotarget
Carolien G F de Kovel, Eva H Brilstra, Marjan J A van Kempen, Ruben Van't Slot, Isaac J Nijman, Zaid Afawi, Peter De Jonghe, Tania Djémié, Renzo Guerrini, Katia Hardies, Ingo Helbig, Rik Hendrickx, Moine Kanaan, Uri Kramer, Anna-Elina E Lehesjoki, Johannes R Lemke, Carla Marini, Davide Mei, Rikke S Møller, Manuela Pendziwiat, Hannah Stamberger, Arvid Suls, Sarah Weckhuysen, Bobby P C Koeleman
BACKGROUND: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation. METHODS: To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients...
September 2016: Molecular Genetics & Genomic Medicine
Federico Sesti
Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. In particular, ROS have been shown to act as modulatory molecules of ion channels-which are key to neuronal excitability-in several physiological processes. However ROS are also fundamental contributors to aging vulnerability. When the level of excess ROS increases in the cell during aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury...
March 2016: Aging and Disease
Niek Verweij, Irene Mateo Leach, Aaron Isaacs, Dan E Arking, Joshua C Bis, Tune H Pers, Marten E Van Den Berg, Leo-Pekka Lyytikäinen, Phil Barnett, Xinchen Wang, Elsayed Z Soliman, Cornelia M Van Duijn, Mika Kähönen, Dirk J Van Veldhuisen, Jan A Kors, Olli T Raitakari, Claudia T Silva, Terho Lehtimäki, Hans L Hillege, Joel N Hirschhorn, Laurie A Boyer, Wiek H Van Gilst, Alvaro Alonso, Nona Sotoodehnia, Mark Eijgelsheim, Rudolf A De Boer, Paul I W De Bakker, Lude Franke, Pim Van Der Harst
The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function...
May 15, 2016: Human Molecular Genetics
Nicholas M Allen, Judith Conroy, Amre Shahwan, Bryan Lynch, Raony G Correa, Sergio D J Pena, Dara McCreary, Tiago R Magalhães, Sean Ennis, Sally A Lynch, Mary D King
Early onset epileptic encephalopathies (EOEEs) represent a significant diagnostic challenge. Newer genomic approaches have begun to elucidate an increasing number of responsible single genes as well as emerging diagnostic strategies. In this single-center study, we aimed to investigate a cohort of children with unexplained EOEE. We performed whole-exome sequencing (WES), targeting a list of 137 epilepsy-associated genes on 50 children with unexplained EOEE. We characterized all phenotypes in detail and classified children according to known electroclinical syndromes where possible...
January 2016: Epilepsia
Yuncui Yu, Jing Wang, Ruiying Kang, Jing Dong, Yuxiang Zhang, Fen Liu, Yuxiang Yan, Rong Zhu, Lili Xia, Xiaoxia Peng, Ling Zhang, Dian He, Herbert Y Gaisano, Zhenwen Chen, Yan He
No abstract text is available yet for this article.
2015: Lipids in Health and Disease
Isabelle Thiffault, David J Speca, Daniel C Austin, Melanie M Cobb, Kenneth S Eum, Nicole P Safina, Lauren Grote, Emily G Farrow, Neil Miller, Sarah Soden, Stephen F Kingsmore, James S Trimmer, Carol J Saunders, Jon T Sack
The epileptic encephalopathies are a group of highly heterogeneous genetic disorders. The majority of disease-causing mutations alter genes encoding voltage-gated ion channels, neurotransmitter receptors, or synaptic proteins. We have identified a novel de novo pathogenic K+ channel variant in an idiopathic epileptic encephalopathy family. Here, we report the effects of this mutation on channel function and heterologous expression in cell lines. We present a case report of infantile epileptic encephalopathy in a young girl, and trio-exome sequencing to determine the genetic etiology of her disorder...
November 2015: Journal of General Physiology
Victoria J Cookson, Sarah L Waite, Paul R Heath, Paul J Hurd, Saurabh V Gandhi, Neil R Chapman
Human parturition is associated with many pro-inflammatory mediators which are regulated by the nuclear factor-kappaB (NF-κB) family of transcription factors. In the present study, we employed a ChIP-on-chip approach to define genomic loci within chromatin of PHM1-31 myometrial cells that were occupied by RelA-containing NF-κB dimers in response to a TNF stimulation of 1 h. In TNF-stimulated PHM1-31 cells, anti-RelA serum enriched 13 300 chromatin regions; importantly, 11 110 regions were also enriched by anti-RelA antibodies in the absence of TNF...
November 2015: Molecular Human Reproduction
Yuncui Yu, Jing Wang, Ruiying Kang, Jing Dong, Yuxiang Zhang, Fen Liu, Yuxiang Yan, Rong Zhu, Lili Xia, Xiaoxia Peng, Ling Zhang, Dian He, Herbert Y Gaisano, Gaisano Herbert, Zhenwen Chen, Yan He
BACKGROUND: In our previous study, we had assessed in the Chinese Han population the association of KCNB1 rs1051295 with metabolic traits indicating metabolic syndrome, and showed that KCNB1 rs1051295 genotype TT was associated with increase of waist to hip ratio (WHR), fasting insulin (FINS), triglycerides (TG) and decreased insulin sensitivity at basal condition. Here, we aimed at detecting whether there were associations between other tag SNPs of KCNB1 and favorable or unfavorable metabolic traits...
2015: Lipids in Health and Disease
Marjaana A Peltola, Juha Kuja-Panula, Johanna Liuhanen, Vootele Võikar, Petteri Piepponen, Tero Hiekkalinna, Tomi Taira, Sari E Lauri, Jaana Suvisaari, Natalia Kulesskaya, Tiina Paunio, Heikki Rauvala
The enormous variability in electrical properties of neurons is largely affected by a multitude of potassium channel subunits. Kv2.1 is a widely expressed voltage-dependent potassium channel and an important regulator of neuronal excitability. The Kv2.1 auxiliary subunit AMIGO constitutes an integral part of the Kv2.1 channel complex in brain and regulates the activity of the channel. AMIGO and Kv2.1 localize to the distinct somatodendritic clusters at the neuronal plasma membrane. Here we have created and characterized a mouse line lacking the AMIGO gene...
January 2016: Schizophrenia Bulletin
Michelle R Mousel, James O Reynolds, Stephen N White
Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion...
2015: PloS One
Ali Torkamani, Kevin Bersell, Benjamin S Jorge, Robert L Bjork, Jennifer R Friedman, Cinnamon S Bloss, Julie Cohen, Siddharth Gupta, Sakkubai Naidu, Carlos G Vanoye, Alfred L George, Jennifer A Kearney
OBJECTIVE: Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic encephalopathies, intellectual disability, and autism. METHODS: We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high-coverage whole exome sequencing (WES) and lower-coverage whole genome sequencing...
October 2014: Annals of Neurology
Fc Howarth, E El Nebrisi, P Jayaprakash, Ma Qureshi, K Parekh, M Oz, Te Adrian
There has been a spectacular rise in the global prevalence of type 2 diabetes mellitus and cardiovascular disease is the major cause of morbidity and mortality in diabetic patients. A variety of diastolic and systolic dysfunctions have been demonstrated in type 2 diabetic heart. The consumption of sugar-sweetened beverages has been linked to rising rates of obesity which in turn is a risk factor for development of type 2 diabetes mellitus. The effects of a sucrose-enriched diet on the pattern of gene expression, contraction and calcium transport in the Goto-Kakizaki (GK) type 2 diabetic rat heart have been investigated...
July 15, 2014: Cardiovascular Research
Federico Sesti, Xilong Wu, Shuang Liu
KCNB1, a voltage-gated potassium (K(+)) channel that conducts a major delayed rectifier current in the brain, pancreas and cardiovascular system is a key player in apoptotic programs associated with oxidative stress. As a result, this protein represents a bona fide drug target for limiting the toxic effects of oxygen radicals. Until recently the consensus view was that reactive oxygen species trigger a pro-apoptotic surge in KCNB1 current via phosphorylation and SNARE-dependent incorporation of KCNB1 channels into the plasma membrane...
May 26, 2014: World Journal of Biological Chemistry
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