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[PMID]:28012039
[Au] Autor:Sánchez-Solano A; Islas AA; Scior T; Paiz-Candia B; Millan-PerezPeña L; Salinas-Stefanon EM
[Ad] Endereço:Laboratorio de Biofísica, Instituto de Fisiología, Universidad Autónoma de Puebla, 14 Sur No. 6301 C.U., 72570, Puebla, Pue, Mexico.
[Ti] Título:Characterization of specific allosteric effects of the Na channel ß1 subunit on the Na 1.4 isoform.
[So] Source:Eur Biophys J;46(5):485-494, 2017 Jul.
[Is] ISSN:1432-1017
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The mechanism of inactivation of mammalian voltage-gated Na channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the ß1 subunit. Na ß1 subunits constitute single-pass transmembrane proteins that form protein-protein associations with pore-forming α subunits to allosterically modulate the Na influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNa 1.4 (skeletal muscle isoform of the rat Na channel) on the α-ß1 functional interaction and showed for the first time that the modulation of ß1 is independent of the IFM motif. We found that: (1) Na 1.4 channels that lack the IFM inactivation particle can undergo a "C-type-like inactivation" albeit in an ultraslow gating mode; (2) ß1 can significantly accelerate the inactivation of Na 1.4 channels in the absence of the IFM motif. Previously, we identified two residues (T109 and N110) on the ß1 subunit that disrupt the α-ß1 allosteric modulation. We further characterized the electrophysiological effects of the double alanine substitution of these residues demonstrating that it decelerates inactivation and recovery from inactivation, abolishes the modulation of steady-state inactivation and induces a current rundown upon repetitive stimulation, thus causing a general loss of function. Our results contribute to delineating the process of the mammalian Na channel inactivation. These findings may be relevant to the design of pharmacological strategies, targeting ß subunits to treat pathologies associated to Na current dysfunction.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.4/química
Canal de Sódio Disparado por Voltagem NAV1.4/metabolismo
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/química
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica
Motivos de Aminoácidos
Animais
Fenômenos Eletrofisiológicos
Espaço Intracelular/metabolismo
Cinética
Modelos Moleculares
Mutação
Canal de Sódio Disparado por Voltagem NAV1.4/genética
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (Voltage-Gated Sodium Channel beta-1 Subunit)
[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:161225
[St] Status:MEDLINE
[do] DOI:10.1007/s00249-016-1193-3


  2 / 108 MEDLINE  
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[PMID]:27848944
[Au] Autor:Trujillano D; Bertoli-Avella AM; Kumar Kandaswamy K; Weiss ME; Köster J; Marais A; Paknia O; Schröder R; Garcia-Aznar JM; Werber M; Brandau O; Calvo Del Castillo M; Baldi C; Wessel K; Kishore S; Nahavandi N; Eyaid W; Al Rifai MT; Al-Rumayyan A; Al-Twaijri W; Alothaim A; Alhashem A; Al-Sannaa N; Al-Balwi M; Alfadhel M; Rolfs A; Abou Jamra R
[Ad] Endereço:Centogene AG, Rostock, Germany.
[Ti] Título:Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
[So] Source:Eur J Hum Genet;25(2):176-182, 2017 Feb.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.
[Mh] Termos MeSH primário: Exoma
Testes Genéticos/métodos
Técnicas de Genotipagem/métodos
Análise de Sequência de DNA/métodos
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Feminino
Flavoproteínas/genética
Testes Genéticos/normas
Técnicas de Genotipagem/normas
Seres Humanos
Lactente
Recém-Nascido
Peptídeos e Proteínas de Sinalização Intracelular/genética
Masculino
Meia-Idade
Proteínas Mitocondriais/genética
Canal de Sódio Disparado por Voltagem NAV1.3/genética
Núcleo Familiar
Fenótipo
Canais de Potássio/genética
Proteínas Tirosina Fosfatases não Receptoras/genética
Protoporfirinogênio Oxidase/genética
Análise de Sequência de DNA/normas
Canais de Sódio/genética
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Flavoproteins); 0 (Intracellular Signaling Peptides and Proteins); 0 (KCTD3 protein, human); 0 (Mitochondrial Proteins); 0 (NAV1.3 Voltage-Gated Sodium Channel); 0 (Potassium Channels); 0 (Preso protein, human); 0 (SCN1B protein, human); 0 (SCN3A protein, human); 0 (Sodium Channels); 0 (Voltage-Gated Sodium Channel beta-1 Subunit); EC 1.3.3.4 (PPOX protein, human); EC 1.3.3.4 (Protoporphyrinogen Oxidase); EC 3.1.3.48 (PTPN23 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatases, Non-Receptor)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170705
[Lr] Data última revisão:
170705
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161117
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2016.146


  3 / 108 MEDLINE  
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[PMID]:27277800
[Au] Autor:Kruger LC; O'Malley HA; Hull JM; Kleeman A; Patino GA; Isom LL
[Ad] Endereço:Department of Pharmacology and.
[Ti] Título:ß1-C121W Is Down But Not Out: Epilepsy-Associated Scn1b-C121W Results in a Deleterious Gain-of-Function.
[So] Source:J Neurosci;36(23):6213-24, 2016 Jun 08.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Voltage-gated sodium channel (VGSC) ß subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, ß subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell-cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC ß1 and ß1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of ß1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for Scn1b-C121W (Scn1b(+/W)) with mice heterozygous for the Scn1b-null allele (Scn1b(+/-)) to determine whether the C121W mutation results in loss-of-function in vivo We found that Scn1b(+/W) mice were more susceptible than Scn1b(+/-) and Scn1b(+/+) mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. ß1-C121W subunits are expressed at the neuronal cell surface in vivo However, despite this, ß1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC α subunits in the brain. ß1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of Scn1b(W/W) mice. These data, together with our previous results showing that ß1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients. SIGNIFICANCE STATEMENT: The mechanisms underlying genetic epilepsy syndromes are poorly understood. Closing this gap in knowledge is essential to the development of new medicines to treat epilepsy. We have used mouse models to understand the mechanism of a mutation in the sodium channel gene SCN1B linked to genetic epilepsy with febrile seizures plus. We report that sodium channel ß1 subunit proteins encoded by this mutant gene are expressed at the surface of neuronal cell bodies; however, they do not associate with the ion channel complex nor are they transported to areas of the axon that are critical for proper neuronal firing. We conclude that this disease-causing mutation is not simply a loss-of-function, but instead results in a deleterious gain-of-function in the brain.
[Mh] Termos MeSH primário: Epilepsia/genética
Neurônios/fisiologia
Polimorfismo de Nucleotídeo Único/genética
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Biotinilação
Células Cultivadas
Córtex Cerebral/citologia
Cisteína/genética
Modelos Animais de Doenças
Epilepsia/etiologia
Epilepsia/patologia
Febre/complicações
Regulação da Expressão Gênica no Desenvolvimento/genética
Imunoprecipitação
Camundongos
Camundongos Transgênicos
Estatísticas não Paramétricas
Triptofano/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Voltage-Gated Sodium Channel beta-1 Subunit); 8DUH1N11BX (Tryptophan); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160610
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0405-16.2016


  4 / 108 MEDLINE  
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[PMID]:26419595
[Au] Autor:Guo G; Cui Y; Chen H; Zhang L; Zhao M; Chen B; Zhang J; Liu Y
[Ad] Endereço:School of Life Science, Shenyang Pharmaceutical University, P.O. Box 17, 103 WenHua Road, Shenyang, 110016, People's Republic of China.
[Ti] Título:Analgesic-antitumor peptide inhibits the migration and invasion of HepG2 cells by an upregulated VGSC ß1 subunit.
[So] Source:Tumour Biol;37(3):3033-41, 2016 Mar.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Analgesic-antitumor peptide (AGAP), one of the scorpion toxin polypeptides, has been shown to have an antitumor activity. Recombinant AGAP (rAGAP) was shown to affect the migration and invasion of HepG2 cells via a voltage-gated sodium channel (VGSC) ß1 subunit. The VGSC ß1 subunit was validated as a cell adhesion molecule (CAM) in human hepatocellular carcinoma (HCC) cell lines. rAGAP suppresses the migration and invasion of HepG2 cells but has no significant effect of human liver HL7702 cells without ß1 subunit expression. rAGAP inhibits the migration and invasion of the cells when the VGSC ß1 subunit is overexpressed in HL7702 cells. To explain these findings, VGSC ß1 subunit messenger RNA (mRNA) and protein levels were measured. The ß1 subunit protein level was upregulated in a dose-dependent manner following treatment with rAGAP while there was no significant change in the mRNA level, so rAGAP might be an active component of the VGSC ß1 subunit.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Peptídeos/farmacologia
Venenos de Escorpião/farmacologia
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/fisiologia
[Mh] Termos MeSH secundário: Movimento Celular/efeitos dos fármacos
Células Hep G2
Seres Humanos
Invasividade Neoplásica
Proteínas Recombinantes/farmacologia
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Peptides); 0 (Recombinant Proteins); 0 (Scorpion Venoms); 0 (Voltage-Gated Sodium Channel beta-1 Subunit)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151001
[St] Status:MEDLINE
[do] DOI:10.1007/s13277-015-4067-x


  5 / 108 MEDLINE  
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[PMID]:26541940
[Au] Autor:Signore S; Sorrentino A; Borghetti G; Cannata A; Meo M; Zhou Y; Kannappan R; Pasqualini F; O'Malley H; Sundman M; Tsigkas N; Zhang E; Arranto C; Mangiaracina C; Isobe K; Sena BF; Kim J; Goichberg P; Nahrendorf M; Isom LL; Leri A; Anversa P; Rota M
[Ad] Endereço:Departments of Anesthesia and Medicine and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Boston, Massachusetts 02115, USA.
[Ti] Título:Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.
[So] Source:Nat Commun;6:8803, 2015 Nov 06.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na(+) current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca(2+) cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca(2+) transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly.
[Mh] Termos MeSH primário: Potenciais de Ação
Envelhecimento/metabolismo
Cálcio/metabolismo
Cardiomiopatias/metabolismo
Ventrículos do Coração/metabolismo
Miocárdio/metabolismo
Miócitos Cardíacos/metabolismo
Retículo Sarcoplasmático/metabolismo
Sódio/metabolismo
[Mh] Termos MeSH secundário: Animais
Cardiomiopatias/fisiopatologia
Colágeno
Modelos Animais de Doenças
Coração/fisiopatologia
Ventrículos do Coração/fisiopatologia
Camundongos
Camundongos Knockout
Contração Miocárdica
Técnicas de Patch-Clamp
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Scn1b protein, mouse); 0 (Voltage-Gated Sodium Channel beta-1 Subunit); 9007-34-5 (Collagen); 9NEZ333N27 (Sodium); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161025
[Lr] Data última revisão:
161025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151107
[St] Status:MEDLINE
[do] DOI:10.1038/ncomms9803


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[PMID]:26129877
[Au] Autor:Hayashi K; Konno T; Tada H; Tani S; Liu L; Fujino N; Nohara A; Hodatsu A; Tsuda T; Tanaka Y; Kawashiri MA; Ino H; Makita N; Yamagishi M
[Ad] Endereço:From the Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (K.H., T.K., H.T., S.T., L.L., N.F., A.N., A.H., T.T., Y.T., M.K., M.Y.); Department of Cardiology, Komatsu Municipal Hospital, Komatsu, Japan (H.I.); and Department of Molecular Physiology
[Ti] Título:Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation.
[So] Source:Circ Arrhythm Electrophysiol;8(5):1095-104, 2015 Oct.
[Is] ISSN:1941-3084
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Few rare variants in atrial fibrillation (AF)-associated genes have been functionally characterized to identify a causal relationship between these variants and development of AF. We here sought to determine the clinical effect of rare variants in AF-associated genes in patients with lone AF and characterized these variants electrophysiologically and bioinformatically. METHODS AND RESULTS: We screened all coding regions in 12 AF-associated genes in 90 patients with lone AF, with an onset of 47±11 years (66 men; mean age, 56±13 years) by high-resolution melting curve analysis and DNA sequencing. The potassium and sodium currents were analyzed using whole-cell patch clamping. In addition to using 4 individual in silico prediction tools, we extended those predictions to an integrated tool (Combined Annotation Dependent Depletion). We identified 7 rare variants in KCNA5, KCNQ1, KCNH2, SCN5A, and SCN1B genes in 8 patients: 2 of 8 probands had a family history of AF. Electrophysiological studies revealed that 2 variants showed a loss-of-function, and 4 variants showed a gain-of-function. Five of 6 variants with electrophysiological abnormalities were predicted as pathogenic by Combined Annotation Dependent Depletion scores. CONCLUSIONS: In our cohort of patients with lone AF, 7 rare variants in cardiac ion channels were identified in 8 probands. A combination of electrophysiological studies and in silico predictions showed that these variants could contribute to the development of lone AF, although further in vivo study is necessary to confirm these results. More than half of AF-associated rare variants showed gain-of-function behavior, which may be targeted using genotype-specific pharmacological therapy.
[Mh] Termos MeSH primário: Fibrilação Atrial/genética
Variação Genética
[Mh] Termos MeSH secundário: Fibrilação Atrial/fisiopatologia
Canal de Potássio ERG1
Técnicas Eletrofisiológicas Cardíacas
Canais de Potássio Éter-A-Go-Go/genética
Feminino
Predisposição Genética para Doença
Genótipo
Seres Humanos
Canais Iônicos/genética
Canal de Potássio KCNQ1/genética
Canal de Potássio Kv1.5/genética
Masculino
Meia-Idade
Mutação/genética
Canal de Sódio Disparado por Voltagem NAV1.5/genética
Técnicas de Patch-Clamp
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ERG1 Potassium Channel); 0 (Ether-A-Go-Go Potassium Channels); 0 (Ion Channels); 0 (KCNH2 protein, human); 0 (KCNQ1 Potassium Channel); 0 (Kv1.5 Potassium Channel); 0 (NAV1.5 Voltage-Gated Sodium Channel); 0 (Voltage-Gated Sodium Channel beta-1 Subunit)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150702
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCEP.114.002519


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[PMID]:25998140
[Au] Autor:Hasdemir C; Payzin S; Kocabas U; Sahin H; Yildirim N; Alp A; Aydin M; Pfeiffer R; Burashnikov E; Wu Y; Antzelevitch C
[Ad] Endereço:Department of Cardiology, Ege University School of Medicine, Izmir, Turkey. Electronic address: can.hasdemir@yahoo.com.
[Ti] Título:High prevalence of concealed Brugada syndrome in patients with atrioventricular nodal reentrant tachycardia.
[So] Source:Heart Rhythm;12(7):1584-94, 2015 Jul.
[Is] ISSN:1556-3871
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Atrioventricular nodal reentrant tachycardia (AVNRT) may coexist with Brugada syndrome (BrS). OBJECTIVES: The present study was designed to determine the prevalence of drug-induced type 1 Brugada ECG pattern (concealed BrS) in patients presenting with clinical spontaneous AVNRT and to investigate their electrocardiographic, electrophysiological, and genetic characteristics. METHODS: Ninety-six consecutive patients without any sign of BrS on baseline electrocardiogram undergoing electrophysiological study and ablation for symptomatic, drug-resistant AVNRT and 66 control subjects underwent an ajmaline challenge to unmask BrS. Genetic screening was performed in 17 patients displaying both AVNRT and BrS. RESULTS: A concealed BrS electrocardiogram was uncovered in 26 of 96 patients with AVNRT (27.1%) and in 3 of 66 control subjects (4.5%) (P ≤ .001). Patients with concealed BrS were predominantly female patients (n=23 [88.5%] vs n=44 [62.9%], P = .015), had higher prevalence of chest pain (n=10 [38.5%] vs n=13 [18.6%], p=0.042), migraine headaches (n=10 [38.5%] vs n=10 [14.2%], p=0.008), and drug-induced initiation and/or worsening of duration and/or frequency of AVNRT (n=4 [15.4%] vs n=1 [1.4%], p=0.006) as compared to patients with AVNRT without BrS. Genetic screening identified 19 mutations or rare variants in 13 genes in 13 of 17 patients with both AVNRT and BrS (yield = 76.5%). Ten of these 13 genotype-positive patients (76.9%) harbored genetic variants known or suspected to cause a loss of function of cardiac sodium channel current (SCN5A, SCN10A, SCN1B, GPD1L, PKP2, and HEY2). CONCLUSION: Our results suggest that spontaneous AVNRT and concealed BrS co-occur, particularly in female patients, and that genetic variants that reduce sodium channel current may provide a mechanistic link between AVNRT and BrS and predispose to expression of both phenotypes.
[Mh] Termos MeSH primário: Ajmalina/farmacologia
Síndrome de Brugada
Ablação por Cateter/métodos
Taquicardia por Reentrada no Nó Atrioventricular
[Mh] Termos MeSH secundário: Adulto
Síndrome de Brugada/induzido quimicamente
Síndrome de Brugada/diagnóstico
Síndrome de Brugada/epidemiologia
Síndrome de Brugada/genética
Síndrome de Brugada/fisiopatologia
Eletrocardiografia/métodos
Técnicas Eletrofisiológicas Cardíacas/métodos
Feminino
Predisposição Genética para Doença
Seres Humanos
Masculino
Meia-Idade
Mutação
Canal de Sódio Disparado por Voltagem NAV1.5/genética
Canal de Sódio Disparado por Voltagem NAV1.8/genética
Prevalência
Taquicardia por Reentrada no Nó Atrioventricular/diagnóstico
Taquicardia por Reentrada no Nó Atrioventricular/epidemiologia
Taquicardia por Reentrada no Nó Atrioventricular/genética
Taquicardia por Reentrada no Nó Atrioventricular/fisiopatologia
Taquicardia por Reentrada no Nó Atrioventricular/cirurgia
Estados Unidos/epidemiologia
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (NAV1.5 Voltage-Gated Sodium Channel); 0 (NAV1.8 Voltage-Gated Sodium Channel); 0 (SCN10A protein, human); 0 (SCN1B protein, human); 0 (SCN5A protein, human); 0 (Voltage-Gated Sodium Channel Blockers); 0 (Voltage-Gated Sodium Channel beta-1 Subunit); 1PON08459R (Ajmaline)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:161222
[Lr] Data última revisão:
161222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150523
[St] Status:MEDLINE


  8 / 108 MEDLINE  
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[PMID]:25847340
[Au] Autor:Vears DF; Dunn KL; Wake SA; Scheffer IE
[Ad] Endereço:Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
[Ti] Título:"It's good to know": experiences of gene identification and result disclosure in familial epilepsies.
[So] Source:Epilepsy Res;112:64-71, 2015 May.
[Is] ISSN:1872-6844
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recognition of the role of genetics in the epilepsies has increased dramatically, impacting on clinical practice across many epilepsy syndromes. There is limited research investigating the impact of gene identification on individuals and families with epilepsy. While research has focused on the impact of delivering genetic information to families at the time of diagnosis in genetic diseases more broadly, little is known about how genetic results in epileptic diseases influences people's lives many years after it has been conveyed. This study used qualitative methods to explore the experience of receiving a genetic result in people with familial epilepsy. Interviews were conducted with individuals with familial epilepsies in whom the underlying genetic mutation had been identified. Recorded interviews underwent thematic analysis. 20 individuals from three families with different epilepsy syndromes and causative genes were interviewed. Multiple generations within families were studied. The mean time from receiving the genetic result prior to interview was 10.9 years (range 5-14 years). Three major themes were identified: 1) living with epilepsy: an individual's experience of the severity of epilepsy in their family influenced their view. 2) Clinical utility of the test: participants expressed varying reactions to receiving a genetic result. While for some it provided helpful information and relief, others were not surprised by the finding given the familial context. Some valued the use of genetic information for reproductive decision-making, particularly in the setting of severely affected family members. While altruistic reasons for participating in genetic research were discussed, participants emphasised the benefit of participation to them and their families. 3) 'Talking about the family genes': individuals reported poor communication between family members about their epilepsy and its genetic implications. The results provide important insights into the family experience of genetic epilepsies and communication within families. This information can be used to inform the development of guidelines for genetic result disclosure and genetic counselling for individuals and families with epilepsies.
[Mh] Termos MeSH primário: Revelação
Epilepsia/genética
Saúde da Família
Mutação/genética
Receptores de GABA-A/genética
Receptores Nicotínicos/genética
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
[Mh] Termos MeSH secundário: Atividades Cotidianas
Tomada de Decisão Clínica
Epilepsia/psicologia
Feminino
Predisposição Genética para Doença/genética
Testes Genéticos
Seres Humanos
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (GABRG2 protein, human); 0 (Receptors, GABA-A); 0 (Receptors, Nicotinic); 0 (SCN1B protein, human); 0 (Voltage-Gated Sodium Channel beta-1 Subunit); 0 (nicotinic acetylcholine receptor alpha4 subunit)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:150407
[Lr] Data última revisão:
150407
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150408
[St] Status:MEDLINE


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[PMID]:25827112
[Au] Autor:Baroni D; Moran O
[Ad] Endereço:Istituto di Biofisica, CNR, Via De Marini 6, 16149 Genova, Italy. Electronic address: dbaroni@ge.ibf.cnr.it.
[Ti] Título:Differential gene expression profiles of two excitable rat cell lines after over-expression of WT- and C121W-ß1 sodium channel subunits.
[So] Source:Neuroscience;297:105-17, 2015 Jun 25.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-dependent sodium channels are membrane proteins essential for cell excitability. They are composed by a pore-forming α-subunit, encoded in mammals by up to nine different genes, and four different ancillary ß-subunits. The expression pattern of the α subunit isoforms confers the distinctive functional and pharmacological properties to different excitable tissues. ß-Subunits are important modulators of channel function and expression. Mutation C121W of the ß1-subunit causes an autosomal dominant epileptic syndrome without cardiac symptoms. In neuroectoderm GH3 and cardiac H9C2 cells, the over-expression of ß1 subunit augments α subunit mRNA and protein levels as well as sodium current density. Interestingly, the introduction of the epileptogenic C121W-ß1 subunit produces additional changes in the α-subunit expression pattern of H9C2 cells, leaving unaltered the sodium channel isoform composition of GH3 cells. The challenge of the present work was to identify those genes that were differentially expressed in response to WT- or C121W-ß1 subunit over-expression in the two rat cell lines under analysis. Hence, we analyzed the total mRNA extracted from control-untransfected and from WT- and C121W-ß1-transfected GH3 and H9C2 cells by DNA-microarray. We found that, in agreement with their different embryonal origin, the over-expression of WT- and C121W-ß1 subunits modifies the expression of different gene sets in GH3 and H9C2 cells. Focusing on the effects of the C121W mutation, we found that it causes the modification of 214 genes, most of them were down-regulated (202) in GH3 cells; on the contrary, it determined the up-regulation of only five genes in H9C2 cells. Interestingly, most genes modified by the C121W ß1 subunit are involved in pivotal processes of the cell such as cellular communication and protein expression. Our results confirm the important role of the sodium channel ß1 subunit in the control of NaCh gene expression, and highlight once more the tissue-specific effect of the C121W mutation.
[Mh] Termos MeSH primário: Cisteína/genética
Mutação/genética
Triptofano/genética
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Transformada
Perfilação da Expressão Gênica
Análise em Microsséries
RNA Mensageiro/metabolismo
Ratos
Transfecção
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Messenger); 0 (Voltage-Gated Sodium Channel beta-1 Subunit); 8DUH1N11BX (Tryptophan); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:150511
[Lr] Data última revisão:
150511
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150402
[St] Status:MEDLINE


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[PMID]:25772295
[Au] Autor:Lin X; O'Malley H; Chen C; Auerbach D; Foster M; Shekhar A; Zhang M; Coetzee W; Jalife J; Fishman GI; Isom L; Delmar M
[Ad] Endereço:Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
[Ti] Título:Scn1b deletion leads to increased tetrodotoxin-sensitive sodium current, altered intracellular calcium homeostasis and arrhythmias in murine hearts.
[So] Source:J Physiol;593(6):1389-407, 2015 Mar 15.
[Is] ISSN:1469-7793
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:KEY POINTS: Na(+) current (INa) results from the integrated function of a molecular aggregate (the voltage-gated Na(+) channel complex) that includes the ß subunit family. Mutations or rare variants in Scn1b (encoding the ß1 and ß1B subunits) have been associated with various inherited arrhythmogenic syndromes, including Brugada syndrome and sudden unexpected death in patients with epilepsy. We used Scn1b null mice to understand better the relation between Scn1b expression, and cardiac electrical function. Loss of Scn1b caused, among other effects, increased amplitude of tetrodotoxin-sensitive INa, delayed after-depolarizations, triggered beats, delayed Ca(2+) transients, frequent spontaneous calcium release events and increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. We propose that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis. ABSTRACT: Na(+) current (INa) is determined not only by the properties of the pore-forming voltage-gated Na(+) channel (VGSC) α subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC ß subunit family. Mutations or rare variants in Scn1b (encoding the ß1 and ß1B subunits) have been associated with various inherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin-sensitive INa but only in the cell midsection, even before full T-tubule formation; the latter occurred concurrent with increased message abundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin-sensitive NaV 1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac-specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after-depolarizations and triggered beats, delayed Ca(2+) transients and frequent spontaneous Ca(2+) release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. Our results suggest that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis in ventricular myocytes.
[Mh] Termos MeSH primário: Potenciais de Ação
Arritmias Cardíacas/genética
Sinalização do Cálcio
Miócitos Cardíacos/fisiologia
Bloqueadores dos Canais de Sódio/farmacologia
Tetrodotoxina/farmacologia
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/genética
[Mh] Termos MeSH secundário: Animais
Arritmias Cardíacas/metabolismo
Células Cultivadas
Deleção de Genes
Camundongos
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/metabolismo
Subunidade beta-1 do Canal de Sódio Disparado por Voltagem/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Scn1b protein, mouse); 0 (Sodium Channel Blockers); 0 (Voltage-Gated Sodium Channel beta-1 Subunit); 4368-28-9 (Tetrodotoxin)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150317
[St] Status:MEDLINE
[do] DOI:10.1113/jphysiol.2014.277699



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