Base de dados : MEDLINE
Pesquisa : D12.776.157.530.400.875.750.200 [Categoria DeCS]
Referências encontradas : 292 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 30 ir para página                         

  1 / 292 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29186148
[Au] Autor:Zhu X; Padmanabhan R; Copeland B; Bridgers J; Ren Z; Kamalakaran S; O'Driscoll-Collins A; Berkovic SF; Scheffer IE; Poduri A; Mei D; Guerrini R; Lowenstein DH; Allen AS; Heinzen EL; Goldstein DB
[Ad] Endereço:Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, United States of America.
[Ti] Título:A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations.
[So] Source:PLoS Genet;13(11):e1007104, 2017 Nov.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p<2.68×10-6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher's exact p = 2.33×10-17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.
[Mh] Termos MeSH primário: Epilepsia/genética
Mutação
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Análise Mutacional de DNA
Feminino
Genes Dominantes
Estudo de Associação Genômica Ampla
Seres Humanos
Masculino
Proteínas Munc18/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Proteínas do Tecido Nervoso/genética
Canais de Potássio/genética
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KCNT1 protein, human); 0 (Munc18 Proteins); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (Nerve Tissue Proteins); 0 (Potassium Channels); 0 (SCN2A protein, human); 0 (STXBP1 protein, human)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007104


  2 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28889641
[Au] Autor:Kuldyushev NA; Berkut AA; Peigneur S; Tytgat J; Grishin EV; Vassilevski AA
[Ad] Endereço:Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
[Ti] Título:Design of sodium channel ligands with defined selectivity - a case study in scorpion alpha-toxins.
[So] Source:FEBS Lett;591(20):3414-3420, 2017 Oct.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Scorpion α-toxins are polypeptides that inhibit voltage-gated sodium channel inactivation. They are divided into mammal, insect and α-like toxins based on their relative activity toward different phyla. Several factors are currently known to influence the selectivity, which are not just particular amino acid residues but also general physical, chemical, and topological properties of toxin structural modules. The objective of this study was to change the selectivity profile of a chosen broadly active α-like toxin, BeM9 from Mesobuthus eupeus, toward mammal-selective. Based on the available information on what determines scorpion α-toxin selectivity, we designed and produced msBeM9, a BeM9 derivative, which was verified to be exclusively active toward mammalian sodium channels and, most importantly, toward the Na 1.2 isoform expressed in the brain.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.2/química
Neurotoxinas/química
Oócitos/efeitos dos fármacos
Proteínas Recombinantes de Fusão/química
Venenos de Escorpião/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Seres Humanos
Insetos/efeitos dos fármacos
Insetos/metabolismo
Camundongos
Modelos Moleculares
Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo
Neurotoxinas/biossíntese
Neurotoxinas/genética
Neurotoxinas/toxicidade
Oócitos/citologia
Oócitos/metabolismo
Ligação Proteica
Engenharia de Proteínas
Domínios e Motivos de Interação entre Proteínas
Estrutura Secundária de Proteína
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/toxicidade
Venenos de Escorpião/biossíntese
Venenos de Escorpião/genética
Venenos de Escorpião/toxicidade
Escorpiões/química
Escorpiões/patogenicidade
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Relação Estrutura-Atividade
Especificidade por Substrato
Tiorredoxinas/biossíntese
Tiorredoxinas/química
Tiorredoxinas/genética
Xenopus laevis
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (Neurotoxins); 0 (Recombinant Fusion Proteins); 0 (Scorpion Venoms); 52500-60-4 (Thioredoxins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170911
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12839


  3 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28880996
[Au] Autor:Steel D; Symonds JD; Zuberi SM; Brunklaus A
[Ad] Endereço:The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom.
[Ti] Título:Dravet syndrome and its mimics: Beyond SCN1A.
[So] Source:Epilepsia;58(11):1807-1816, 2017 Nov.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions. METHODS: Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS-like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Genes that have been reported to cause DS-like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role. SIGNIFICANCE: Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene-based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas/diagnóstico
Epilepsias Mioclônicas/genética
Mutação/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
[Mh] Termos MeSH secundário: Seres Humanos
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Fenótipo
Receptores de GABA-A/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GABRA1 protein, human); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (Receptors, GABA-A); 0 (SCN1A protein, human); 0 (SCN2A protein, human); 0 (SCN8A protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13889


  4 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28784306
[Au] Autor:Yamagata T; Ogiwara I; Mazaki E; Yanagawa Y; Yamakawa K
[Ad] Endereço:Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
[Ti] Título:Nav1.2 is expressed in caudal ganglionic eminence-derived disinhibitory interneurons: Mutually exclusive distributions of Nav1.1 and Nav1.2.
[So] Source:Biochem Biophys Res Commun;491(4):1070-1076, 2017 Sep 30.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nav1.1 and Nav1.2 are the voltage-gated sodium channel pore-forming alpha I and II subunits, encoded by the genes SCN1A and SCN2A. Although mutations of both genes have similarly been described in patients with epilepsy, autism and/or intellectual disability, their expression sites in brain are largely distinct. Nav1.1 was shown to be expressed dominantly in parvalbumin (PV)-positive or somatostatin (SST)-positive inhibitory neurons and in a sparsely-distributed subpopulation of excitatory neurons. In contrast, Nav1.2 has been reported to be dominantly expressed in excitatory neurons. Here we show that Nav1.2 is also expressed in caudal ganglionic eminence (CGE)-derived inhibitory neurons, and expressions of Nav1.1 and Nav1.2 are mutually-exclusive in many of brain regions including neocortex, hippocampus, cerebellum, striatum and globus pallidus. In neocortex at postnatal day 15, in addition to the expression in excitatory neurons we show that Nav1.2 is expressed in reelin (RLN)-positive/SST-negative inhibitory neurons that are presumably single-bouquet cells because of their cortical layer I-limited distribution, and vasoactive intestinal peptide (VIP)-positive neurons that would be multipolar cell because of their layer I/II margin and layer VI distribution. Although Nav1.2 has previously been reported to be expressed in SST-positive cells, we here show that Nav1.2 is not expressed in either of PV-positive or SST-positive inhibitory neurons. PV-positive and SST-positive inhibitory neurons derive from medial ganglionic eminence (MGE) and innervate excitatory neurons, while VIP-positive and RLN-positive/SST-negative inhibitory neurons derive from CGE, innervate on inhibitory neurons and play disinhibitory roles in the neural network. Our results therefore indicate that, while Nav1.1 is expressed in MEG-derived inhibitory neurons, Nav1.2 is expressed in CGE-derived disinhibitory interneurons in addition to excitatory neurons. These findings should contribute to understanding of the pathology of neurodevelopmental diseases caused by SCN2A mutations.
[Mh] Termos MeSH primário: Interneurônios/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.1/biossíntese
Canal de Sódio Disparado por Voltagem NAV1.2/biossíntese
[Mh] Termos MeSH secundário: Animais
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170809
[St] Status:MEDLINE


  5 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28683073
[Au] Autor:Li T; Lu G; Chiang EY; Chernov-Rogan T; Grogan JL; Chen J
[Ad] Endereço:Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America.
[Ti] Título:High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE.
[So] Source:PLoS One;12(7):e0180154, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ion channels regulate a variety of physiological processes and represent an important class of drug target. Among the many methods of studying ion channel function, patch clamp electrophysiology is considered the gold standard by providing the ultimate precision and flexibility. However, its utility in ion channel drug discovery is impeded by low throughput. Additionally, characterization of endogenous ion channels in primary cells remains technical challenging. In recent years, many automated patch clamp (APC) platforms have been developed to overcome these challenges, albeit with varying throughput, data quality and success rate. In this study, we utilized SyncroPatch 768PE, one of the latest generation APC platforms which conducts parallel recording from two-384 modules with giga-seal data quality, to push these 2 boundaries. By optimizing various cell patching parameters and a two-step voltage protocol, we developed a high throughput APC assay for the voltage-gated sodium channel Nav1.7. By testing a group of Nav1.7 reference compounds' IC50, this assay was proved to be highly consistent with manual patch clamp (R > 0.9). In a pilot screening of 10,000 compounds, the success rate, defined by > 500 MΩ seal resistance and >500 pA peak current, was 79%. The assay was robust with daily throughput ~ 6,000 data points and Z' factor 0.72. Using the same platform, we also successfully recorded endogenous voltage-gated potassium channel Kv1.3 in primary T cells. Together, our data suggest that SyncroPatch 768PE provides a powerful platform for ion channel research and drug discovery.
[Mh] Termos MeSH primário: Ensaios de Triagem em Larga Escala/métodos
Potenciais da Membrana/fisiologia
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Técnicas de Patch-Clamp/métodos
Bloqueadores dos Canais de Potássio/farmacologia
Bloqueadores dos Canais de Sódio/farmacologia
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetulus
Avaliação Pré-Clínica de Medicamentos
Expressão Gênica
Ensaios de Triagem em Larga Escala/instrumentação
Canal de Potássio Kv1.3/deficiência
Canal de Potássio Kv1.3/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.3/genética
Canal de Sódio Disparado por Voltagem NAV1.3/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.5/genética
Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/genética
Técnicas de Patch-Clamp/instrumentação
Cultura Primária de Células
Ratos
Canais de Sódio/genética
Canais de Sódio/metabolismo
Linfócitos T/citologia
Linfócitos T/efeitos dos fármacos
Linfócitos T/metabolismo
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kv1.3 Potassium Channel); 0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.3 Voltage-Gated Sodium Channel); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (NAV1.5 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Potassium Channel Blockers); 0 (SCN1A protein, human); 0 (SCN3A protein, human); 0 (SCN4A protein, human); 0 (SCN5A protein, human); 0 (SCN8A protein, human); 0 (SCN9A protein, human); 0 (Sodium Channel Blockers); 0 (Sodium Channels)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180154


  6 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28518218
[Au] Autor:Holland KD; Bouley TM; Horn PS
[Ad] Endereço:Departments of Pediatrics and Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio, U.S.A.
[Ti] Título:Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy.
[So] Source:Epilepsia;58(7):1190-1198, 2017 Jul.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy. METHODS: Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. RESULTS: Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52-0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a combination of algorithms increased the accuracy to 0.92. SIGNIFICANCE: Potentially pathogenic variants are present in population-based sources. Most computational algorithms overestimate pathogenicity; however, a weighted combination of several algorithms increased classification accuracy to >0.90.
[Mh] Termos MeSH primário: Algoritmos
Simulação por Computador
Epilepsia/genética
Epilepsia/fisiopatologia
Variação Genética/genética
Mutação de Sentido Incorreto/genética
Canal de Sódio Disparado por Voltagem NAV1.1/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.6/genética
Canais de Sódio/genética
[Mh] Termos MeSH secundário: Análise Mutacional de DNA
Bases de Dados Genéticas
Predisposição Genética para Doença/genética
Seres Humanos
Lactente
Fenótipo
Valor Preditivo dos Testes
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.1 Voltage-Gated Sodium Channel); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (NAV1.6 Voltage-Gated Sodium Channel); 0 (SCN1A protein, human); 0 (SCN2A protein, human); 0 (SCN8A protein, human); 0 (Sodium Channels)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13798


  7 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28379373
[Au] Autor:Wolff M; Johannesen KM; Hedrich UBS; Masnada S; Rubboli G; Gardella E; Lesca G; Ville D; Milh M; Villard L; Afenjar A; Chantot-Bastaraud S; Mignot C; Lardennois C; Nava C; Schwarz N; Gérard M; Perrin L; Doummar D; Auvin S; Miranda MJ; Hempel M; Brilstra E; Knoers N; Verbeek N; van Kempen M; Braun KP; Mancini G; Biskup S; Hörtnagel K; Döcker M; Bast T; Loddenkemper T; Wong-Kisiel L; Baumeister FM; Fazeli W; Striano P; Dilena R; Fontana E; Zara F; Kurlemann G; Klepper J; Thoene JG; Arndt DH; Deconinck N; Schmitt-Mechelke T; Maier O; Muhle H; Wical B; Finetti C
[Ad] Endereço:Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
[Ti] Título:Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.
[So] Source:Brain;140(5):1316-1336, 2017 May 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
[Mh] Termos MeSH primário: Epilepsia/tratamento farmacológico
Epilepsia/genética
Epilepsia/fisiopatologia
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia
Transtornos do Neurodesenvolvimento/genética
Bloqueadores dos Canais de Sódio/uso terapêutico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idade de Início
Criança
Pré-Escolar
Dinamarca/epidemiologia
Epilepsia/epidemiologia
Feminino
Seres Humanos
Lactente
Masculino
Mutação
Fenótipo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (SCN2A protein, human); 0 (Sodium Channel Blockers)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx054


  8 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28343066
[Au] Autor:Hovey L; Fowler CA; Mahling R; Lin Z; Miller MS; Marx DC; Yoder JB; Kim EH; Tefft KM; Waite BC; Feldkamp MD; Yu L; Shea MA
[Ad] Endereço:Department of Biochemistry, University of Iowa, 52242-1109 Iowa City, United States.
[Ti] Título:Calcium triggers reversal of calmodulin on nested anti-parallel sites in the IQ motif of the neuronal voltage-dependent sodium channel Na 1.2.
[So] Source:Biophys Chem;224:1-19, 2017 May.
[Is] ISSN:1873-4200
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Several members of the voltage-gated sodium channel family are regulated by calmodulin (CaM) and ionic calcium. The neuronal voltage-gated sodium channel Na 1.2 contains binding sites for both apo (calcium-depleted) and calcium-saturated CaM. We have determined equilibrium dissociation constants for rat Na 1.2 IQ motif [IQRAYRRYLLK] binding to apo CaM (~3nM) and (Ca ) -CaM (~85nM), showing that apo CaM binding is favored by 30-fold. For both apo and (Ca ) -CaM, NMR demonstrated that Na 1.2 IQ motif peptide (Na 1.2 ) exclusively made contacts with C-domain residues of CaM (CaM ). To understand how calcium triggers conformational change at the CaM-IQ interface, we determined a solution structure (2M5E.pdb) of (Ca ) -CaM bound to Na 1.2 . The polarity of (Ca ) -CaM relative to the IQ motif was opposite to that seen in apo CaM -Na 1.2 (2KXW), revealing that CaM recognizes nested, anti-parallel sites in Na 1.2 . Reversal of CaM may require transient release from the IQ motif during calcium binding, and facilitate a re-orientation of CaM allowing interactions with non-IQ Na 1.2 residues or auxiliary regulatory proteins interacting in the vicinity of the IQ motif.
[Mh] Termos MeSH primário: Motivos de Aminoácidos
Cálcio/farmacologia
Calmodulina/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.2/química
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Cálcio/metabolismo
Proteínas do Tecido Nervoso/química
Ressonância Magnética Nuclear Biomolecular
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calmodulin); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (Nerve Tissue Proteins); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170327
[St] Status:MEDLINE


  9 / 292 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28334922
[Au] Autor:Mishra V; Karumuri BK; Gautier NM; Liu R; Hutson TN; Vanhoof-Villalba SL; Vlachos I; Iasemidis L; Glasscock E
[Ad] Endereço:Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA.
[Ti] Título:Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).
[So] Source:Hum Mol Genet;26(11):2091-2103, 2017 Jun 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility.
[Mh] Termos MeSH primário: Epilepsia/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo
[Mh] Termos MeSH secundário: Animais
Biomarcadores
Encéfalo/fisiopatologia
Morte Súbita
Modelos Animais de Doenças
Eletrocardiografia
Eletroencefalografia
Epilepsia/complicações
Genótipo
Coração/fisiopatologia
Frequência Cardíaca
Canal de Potássio Kv1.1/genética
Canal de Potássio Kv1.1/metabolismo
Camundongos
Camundongos Knockout
Convulsões/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Kcna1 protein, mouse); 0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (Scn2a1 protein, mouse); 147173-20-4 (Kv1.1 Potassium Channel)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx104


  10 / 292 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28255270
[Au] Autor:He F; Peng Y; Yang Z; Ge Z; Tian Y; Ma T; Li H
[Ad] Endereço:Department of Histology and Embryology, Third Military Medical University, Chongqing, China.; Battalion 5 of Cadet Brigade, Third Military Medical University, Chongqing, China.
[Ti] Título:Activated ClC-2 Inhibits p-Akt to Repress Myelination in GDM Newborn Rats.
[So] Source:Int J Biol Sci;13(2):179-188, 2017.
[Is] ISSN:1449-2288
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:This study aims to investigate the effect and mechanism of type 2 voltage-gated chloride channel (ClC-2) on myelin development of newborn rats' cerebral white matter with gestational diabetes mellitus (GDM). In this study, GDM model was induced in late pregnant rat model. The alteration of ClC-2 expression in various developmental stages of cerebral white matter with/without being exposed to high glucose was analyzed using RT-PCR, active oxygen detection, TUNEL staining, Western Blot as well as immuno-histochemical staining. Our results showed that ClC-2 mRNA and protein expressions in GDM group were significantly increased in white matter of fetal rats after E18 stage, and elevated the level of TNF-α and iNOS in white matter at P0 and P3 stage of newborn rats. Meanwhile, In GDM group, reactive oxygen species (ROS) levels of the white matter at E18, P0, and P3 stage were significantly higher than control group. Furthermore, the expression level of myelin transcription factor Olig2 at P0 stage and CNPase at P3 stage were strikingly lower than that of the control group. In GDM group, ClC-2 expression in the corpus callosum (CC) and cingulate gyrus (CG) regains, and TUNEL positive cell number were increased at P0 and P3 stage. However, PDGFα positive cell number at P0 stage and CNPase expression at P3 stage were significantly decreased. Caspase-3 was also increased in those white matter regions in GDM group, but p-Akt expression was inhibited. While DIDS (a chloride channel blocker) can reverse these changes. In conclusion, ClC-2 and caspase-3 were induced by GDM, which resulted in apoptosis and myelination inhibition. The effect was caused by repressing PI3K-Akt signaling pathway. Application of ClC-2 inhibitor DIDS showed protective effects on cerebral white matter damage stimulated by high glucose concentration.
[Mh] Termos MeSH primário: Diabetes Gestacional/metabolismo
Bainha de Mielina/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Apoptose/genética
Apoptose/fisiologia
Western Blotting
Caspase 3/genética
Caspase 3/metabolismo
Corpo Caloso/metabolismo
Diabetes Gestacional/genética
Feminino
Giro do Cíngulo/metabolismo
Imuno-Histoquímica
Marcação In Situ das Extremidades Cortadas
Masculino
Camundongos
Bainha de Mielina/genética
Canal de Sódio Disparado por Voltagem NAV1.2/genética
Óxido Nítrico Sintase Tipo II/genética
Óxido Nítrico Sintase Tipo II/metabolismo
Fosfatidilinositol 3-Quinases/genética
Gravidez
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Ratos
Ratos Sprague-Dawley
Espécies Reativas de Oxigênio/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Fator de Necrose Tumoral alfa/genética
Fator de Necrose Tumoral alfa/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.2 Voltage-Gated Sodium Channel); 0 (Reactive Oxygen Species); 0 (Tumor Necrosis Factor-alpha); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (Caspase 3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170304
[St] Status:MEDLINE
[do] DOI:10.7150/ijbs.17716



página 1 de 30 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde