掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1038/s41467-019-09954-9

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その他リンク： http://www.nature.com/articles/s41467-019-09954-9

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1038/s42003-018-0099-2

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その他リンク： http://www.nature.com/articles/s42003-018-0099-2

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.eplepsyres.2018.08.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

An accumulating body of experimental evidence has implicated hippocampal replay occurring within sharp wave ripples (SPW-Rs) as crucial for learning and memory in healthy subjects. This raises speculation that neurological disorders impairing memory disrupt either SPW-Rs or their underlying neuronal activity. We report that mice heterozygous for the gene Scn2a, a site of frequent de novo mutations in humans with intellectual disability, displayed impaired spatial memory. While we observed no changes during encoding, to either single place cells or cell assemblies, we identified abnormalities restricted to SPW-R episodes that manifest as decreased cell assembly reactivation strengths and truncated hippocampal replay sequences. Our results suggest that alterations to hippocampal replay content may underlie disease-associated memory deficits.

DOI： 10.1038/s41593-018-0163-8

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Academic Press Inc.  

Loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Nav1.1, have been described in the majority of Dravet syndrome patients presenting with epileptic seizures, hyperactivity, autistic traits, and cognitive decline. We previously reported predominant Nav1.1 expression in parvalbumin-expressing (PV+) inhibitory neurons in juvenile mouse brain and observed epileptic seizures in mice with selective deletion of Scn1a in PV+ cells mediated by PV-Cre transgene expression (Scn1afl/+/PV-Cre-TG). Here we investigate the behavior of Scn1afl/+/PV-Cre-TG mice using a comprehensive battery of behavioral tests. We observed that Scn1afl/+/PV-Cre-TG mice display hyperactive behavior, impaired social novelty recognition, and altered spatial memory. We also generated Scn1afl/+/SST-Cre-KI mice with a selective Scn1a deletion in somatostatin-expressing (SST+) inhibitory neurons using an SST-IRES-Cre knock-in driver line. We observed that Scn1afl/+/SST-Cre-KI mice display no spontaneous convulsive seizures and that Scn1afl/+/SST-Cre-KI mice have a lowered threshold temperature for hyperthermia-induced seizures, although their threshold values are much higher than those of Scn1afl/+/PV-Cre-TG mice. We finally show that Scn1afl/+/SST-Cre-KI mice exhibited no noticeable behavioral abnormalities. These observations suggest that impaired Nav1.1 function in PV+ interneurons is critically involved in the pathogenesis of hyperactivity, autistic traits, and cognitive decline, as well as epileptic seizures, in Dravet syndrome.

DOI： 10.1016/j.nbd.2018.01.009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

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 Ifil 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. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.08.013

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担当区分：筆頭著者,　責任著者  

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担当区分：筆頭著者,　責任著者  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/ncomms6525

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

Dravet syndrome is a severe epileptic encephalopathy mainly caused by heterozygous mutations in the SCN1A gene encoding a voltage-gated sodium channel Nav1.1. We previously reported dense localization of Nav1.1 in parvalbumin (PV)-positive inhibitory interneurons in mice and abnormal firing of those neurons in Nav1.1-deficient mice. In the present study, we investigated the physiologic consequence of selective Nav1.1 deletion in mouse global inhibitory neurons, forebrain excitatory neurons or PV cells, using vesicular GABA transporter (VGAT)-Cre, empty spiracles homolog 1 (Emx1)-Cre or PV-Cre recombinase drivers. We show that selective Nav1.1 deletion using VGAT-Cre causes epileptic seizures and premature death that are unexpectedly more severe than those observed in constitutive Nav1.1-deficient mice. Nav1.1 deletion using Emx1-Cre does not cause any noticeable abnormalities in mice; however, the severe lethality observed with VGAT-Cre-driven Nav1.1 deletion is rescued by additional Nav1.1 deletion using Emx1-Cre. In addition to predominant expression in PV interneurons, we detected Nav1.1 in subpopulations of excitatory neurons, including entorhino-hippocampal projection neurons, a subpopulation of neocortical layer V excitatory neurons, and thalamo-cortical projection neurons. We further show that even minimal selective Nav1.1 deletion, using PV-Cre, is sufficient to cause spontaneous epileptic seizures and ataxia in mice. Overall, our results indicate that functional impairment of PV inhibitory neurons with Nav1.1 haploinsufficiency contributes to the epileptic pathology of Dravet syndrome, and show for the first time that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on the pathology.

DOI： 10.1093/hmg/ddt331

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：10  

Objective:Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP.Methods:Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed.Results:We observed a 2-fold increase in both transient and persistent Na+ current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na+ current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia.Interpretation:These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients. © 2013 Auerbach et al.

DOI： 10.1371/journal.pone.0077843

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Dravet syndrome is an intractable epileptic encephalopathy characterized by early onset epileptic seizures followed by cognitive decline, hyperactivity, autistic behaviors and ataxia. Most Dravet syndrome patients possess heterozygous mutations of SCN1A gene encoding voltage-gated sodium channel alpha(1) subunit (Na(v)1.1). We have previously reported that mice heterozygous for a nonsense mutation in Scn1a developed early onset epileptic seizures. However, the learning ability and sociability of the mice remained to be investigated. In the present study, we subjected heterozygous Scn1a mice to a comprehensive behavioral test battery. We found that while heterozygous Scn1a mice had lowered spontaneous motor activity in home cage, they were hyperactive in novel environments. Moreover, the mice had low sociability and poor spatial learning ability that correspond to the autistic behaviors and cognitive decline seen in Dravet syndrome patients. These results suggest that Na(v)1.1 haploinsufficiency intrinsically contributes to not only epileptic seizures but also lowered sociability and learning impairment in heterozygous Scn1a mutant mice, as it should also be the case in patients with Dravet syndrome. (c) 2012 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.nbd.2012.08.003

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：12  

DOI： 10.1111/epi.12040

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Purpose: We previously reported a mutant mouse carrying a severe myoclonic epilepsy in infancy (SMEI) mutation in Scn1a. In this study, we examined the susceptibility to hyperthermia-induced seizures of heterozygous Scn1a mutant mice (Scn1aRX/+) and wild-type (Scn1a+/+) mice. Then we assessed the efficacy of stiripentol (STP) monotherapy versus STP and clobazam (CLB) combination therapy to prevent hyperthermia-induced seizures in Scn1aRX/+ mice. Methods: The seizure-inducing body temperatures in Scn1aRX/+ mice and age-matched Scn1a+/+ mice were compared in three age groups (1 month, 35 months, > 6 months). Then STP, CLB, or STP + CLB was administered intraperitoneally to Scn1aRX/+ mice of two age groups (p1M, aged 1 month; p5M, aged 510 months). The efficacy of medications was assessed by comparing the seizure-inducing body temperature and the duration of seizures. Key Findings: The seizure-inducing body temperature was significantly lower in Scn1aRX/+ than in Scn1a+/+ mice for all age groups (p < 0.01). The seizure-inducing body temperature was significantly elevated after administration of STP in p1M (p < 0.05) but not in p5M (p > 0.05), and it was significantly elevated after administration of CLB in both age groups (p < 0.05). The seizure-inducing body temperature was significantly higher after administration of STP + CLB than after administration of CLB in p5M (p < 0.05). Significance: Scn1a RX/+ mice have increased susceptibility to hyperthermia-induced seizure in all age groups. STP monotherapy is effective in preventing hyperthermia-induced seizures in Scn1aRX/+ mice aged 1 month, but not in those aged 5 months and older. When used in combination therapy with CLB, STP inhibits the metabolism of CLB and probably synergistically enhances the anticonvulsant effect in mice aged 1 month.

DOI： 10.1111/j.1528-1167.2012.03497.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Nav1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Nav1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the beta 1 subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI.

DOI： 10.1111/j.1528-1167.2012.03467.x

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Georg Thieme Verlag KG  

DOI： 10.1055/s-0031-1279725

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担当区分：筆頭著者,　責任著者  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Mutations involving the voltage-gated sodium channel alpha(I) gene SCN1A are major genetic causes of childhood epileptic disorders, as typified by Dravet syndrome. Here we investigated the upstream regions of the SCN1A 5' noncoding exons and found two major regions with promoter activity. These two major promoters were simultaneously active in various brain regions and in most neurons. Using multiplex ligation-dependent probe amplification (MLPA) assays with probes for the 5' noncoding exons, their upstream regions, and all coding exons of SCN1A, we investigated 130 epileptic patients who did not show any SCN1A mutations by sequence analysis of all coding exons and exon intron boundaries. Among 71 Dravet syndrome patients, we found two patients with heterozygous microdeletions removing the 5' noncoding exons and regions with promoter activity but not affecting the coding exons. We also identified four patients with deletions/duplication in the coding region. One patient with symptomatic focal epilepsy also showed a deletion in the coding region. This study provides the first case of microdeletion limited to the SCN1A 5' promoter region with the coding sequence preserved, and indicates the critical involvement of this upstream region in the molecular pathology of Dravet syndrome. Hum Mutat 31:820-829, 2010. (C) 2010 Wiley-Liss, Inc.

DOI： 10.1002/humu.21275

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Background: Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances.
Methods: We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations.
Results: We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (a similar to 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (a similar to 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused a similar to 14-mV hyperpolarizing shift in the voltage dependence of activation.
Conclusions: The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels. Neurology (R) 2009;73:1046-1053

DOI： 10.1212/WNL.0b013e3181b9cebc

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

We investigated the roles of mutations in voltage-gated sodium channel alpha 1 subunit gene (SCN1A) in epilepsies and psychiatric disorders. The SCN1A gene was screened for mutations in three unrelated Japanese families with generalized epilepsy with febrile seizure plus (GEFS+), febrile seizure with myoclonic seizures, or intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC). In the family with GEFS+, one individual was affected with panic disorder and seizures, and another individual was diagnosed with Asperger syndrome and seizures. The novel mutation V13661 was found in all probands and patients with psychiatric disorders of the three families. These results suggest that SCN1A mutations may confer susceptibility to psychiatric disorders in addition to variable epileptic seizures. Unidentified modifiers may play critical roles in determining the ultimate phenotype of patients with sodium channel mutations. (c) 2007 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.eplepsyres.2007.03.018

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC NEUROSCIENCE  

Loss-of-function mutations in human SCN1A gene encoding Na(v)1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy. Here, we generated and characterized a knock-in mouse line with a loss-of-function nonsense mutation in the Scn1a gene. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. Immunohistochemical analyses revealed that, in the developing neocortex, Na(v)1.1 was clustered predominantly at the axon initial segments of parvalbumin-positive (PV) interneurons. In heterozygous knock-in mice, trains of evoked action potentials in these fast-spiking, inhibitory cells exhibited pronounced spike amplitude decrement late in the burst. Our data indicate that Na(v)1.1 plays critical roles in the spike output from PV interneurons and, furthermore, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice.

DOI： 10.1523/JNEUROSCI.5270-06.2007

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Temporal lobe epilepsy (TLE) has a multifactorial etiology involving developmental, environmental, and genetic components. Here, we report a voltage-gated potassium channel gene mutation found in a TLE patient, namely a K(v)4.2 truncation mutation. K(v)4.2 channels, encoded by the A'CND2 gene, mediate A currents in the brain. The identified mutation corresponds to an N587fsX1 amino acid change, predicted to produce a truncated K(v)4.2 protein lacking the last 44 amino acids in the carboxyl terminal. Electrophysiological analysis indicates attenuated K+ current density in cells expressing this K(v)4.2-N587fsX1 mutantchannel, which is consistent with a model ofaberrant neuronal excitabilit, * v characteristic of TLE. Our observations, together with other lines ofevidence, raise the intriguing possibility of a role for KCjVD2 in the etiology of TLE. (c) 2006 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.nbd.2006.07.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Purpose: To investigate the genetic background of familial severe myoclonic epilepsy in infancy (SMEI) cases.
Methods: We performed mutation analyses of the sodium-channel gene SCN1A in two Japanese brothers with clinical features of SMEI and their parents, who had no history of febrile and epileptic seizures.
Results: Each patient showed nucleotide changes (c.[730G > T; 735G > T; 736A > T]) in the coding exon 6 of SCN1A that led to a truncation of the channel protein. Their father showed no mutations, but their mother showed the same mutation in a subpopulation of lymphocytes.
Conclusions: The maternal mosaicism explains the identical SCN1A mutations in the two brothers. This highlights the importance of investigating parental mosaicism even in sporadic SMEI cases.

DOI： 10.1111/j.1528-1167.2006.00645.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Mutations in SCN1A, the gene encoding the brain voltage-gated sodium channel alpha(1) subunit (Na(V)1.1), are associated with genetic forms of epilepsy, including generalized epilepsy with febrile seizures plus (GEFS+ type 2), severe myoclonic epilepsy of infancy (SMEI) and related conditions. Several missense SCN1A mutations have been identified in probands affected by the syndrome of intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), which bears similarity to SMEI. To test whether ICEGTC arises from molecular mechanisms similar to those involved in SMEI, we characterized eight ICEGTC missense mutations by whole-cell patch clamp recording of recombinant human SCN1A heterologously expressed in cultured mammalian cells. Two mutations (G979R and T1709I) were non-functional. The remaining alleles (T808S, V983A, N1011I, V1611F, P1632S and F1808L) exhibited measurable sodium current, but had heterogeneous biophysical phenotypes. Mutant channels exhibited lower (V983A, N1011I and F1808L), greater (T808S) or similar (V1611F and P1632S) peak sodium current densities compared with wild-type (WT) SCN1A. Three mutations (V1611F, P1632S and F1808L) displayed hyperpolarized conductance-voltage relationships, while V983A exhibited a strong depolarizing shift in the voltage dependence of activation. All mutants except T808S had hyperpolarized shifts in the voltage dependence of steady-state channel availability. Three mutants (V1611F, P1632S and F1808L) exhibited persistent sodium current ranging from similar to 1-3% of peak current amplitude that was significantly greater than WT-SCN1A. Several mutants had impaired slow inactivation, with V983A showing the most prominent effect. Finally, all of the functional alleles exhibited reduced use-dependent channel inhibition. In summary, SCN1A mutations associated with ICEGTC result in a wide spectrum of biophysical defects, including mild-to-moderate gating impairments, shifted voltage dependence and reduced use dependence. The constellation of biophysical abnormalities for some mutants is distinct from those previously observed for GEFS+ and SMEI, suggesting possible, but complex, genotype-phenotype correlations.

DOI： 10.1113/jphysiol.2005.094326

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC MICROBIOLOGY  

U small nuclear RNAs (snRNAs) and mRNAs are both transcribed by RNA polymerase II (Pol II), but the snRNAs have unusual TATA-less promoters and are neither spliced nor polyadenylated; instead, 3' processing is directed by a highly conserved 3' end formation signal that requires initiation from an snRNA promoter. Here we show that the C-terminal domain (CTD) of Pol II is required for efficient U2 snRNA transcription, as it is for mRNA transcription. However, CTD kinase inhibitors, such as 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), that block mRNA elongation do not affect U2 transcription, although 3' processing of the U2 primary transcript is impaired. We show further that U2 transcription is preferentially inhibited by low doses of UV irradiation or actinomycin D, which induce CTD kinase activity, and that LTV inhibition can be rescued by treatment with DRB or H7. We propose that Pol II complexes transcribing snRNAs and mRNAs have distinct CTD phosphorylation patterns. mRNA promoters recruit factors including kinases that hyperphosphorylate the CTD, and the CTD in turn recruits proteins needed for mRNA splicing and polyadenylation. We predict that snRNA promoters recruit factors including a CTD kinase(s) whose snRNA-specific phosphorylation pattern recruits factors required for promoter-coupled 3' end formation.

DOI： 10.1128/MCB.24.2.846-855.2004

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT  

We have identified a new superfamily of vertebrate short interspersed repetitive elements (SINEs), designated V-SINEs, that are widespread in fishes and frogs. Each V-SINE includes a central conserved domain preceded by a 5'-end tRNA-related', region and followed by a potentially recombinagenic (TG)(n) tract, with a 3' tail derived from the 3' untranslated' region (UTR) of the corresponding partner long interspersed repetitive element (LINE) that encodes a functional reverse transcriptase. The central domain is strongly conserved and is even found in SINEs in the lamprey genome, suggesting that V-SINEs might be similar to550 Myr old or older in view of the timing of divergence of the lamprey lineage from the bony fish lineage. The central conserved domain might have been subject to some form of positive selection. Although the contemporary 3' tails of V-SINEs differ from one another, it is possible that the original 3' tail might have been replaced, via recombination, by the 3' tails of more active partner LINES, thereby retaining retropositional activity and the ability to survive for long periods on the evolutionary time scale. It seems plausible that V-SINEs may have some function(s) that have been maintained by the coevolution of SINEs and LINES during the evolution of vertebrates.

DOI： 10.1101/gr.212302

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SOC MOLECULAR BIOLOGY EVOLUTION  

Some previously unidentified short interspersed repetitive elements (SINEs) and long interspersed repetitive element (LINEs) were isolated from various higher elasmobranchs (sharks, skates, and rays) and characterized. These SINEs, members of the HE1 SINE family, were tRNA-derived and were widespread in higher elasmobranchs. The 3'-tail region of this SINE family was strongly conserved among elasmobranchs. The LINEs, members of the HER1 LINE family, encoded an amino acid sequence similar to that encoded by the chicken CR1 LINE family, and they contained a strongly conserved 3'-tail region in the 3' untranslated region. This tail region of the HER1 LINE family was almost identical to that of the HE1 SINE family. Thus, the HEL SINE family and the HER1 LINE family provide a clear example of a pair of SINEs and LINEs that share the same tail region. Conservation of the secondary structures of the tail regions, as well as of the nucleotide sequences, between the HE1 SINE family and HERL LINE family during evolution suggests that SINEs utilize the enzymatic machinery for retroposition of LINEs through the recognition of higher-order structures of the conserved 3'-tail region. A discussion is presented of the parasitism of SINEs on LINEs during the evolution of these retroposons.

DOI： 10.1093/oxfordjournals.molbev.a026214

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

There are now five reported examples in which the 3' ends of tRNA-derived SINEs are derived from the 3' ends of LINEs. These examples include representative sequences from turtles, fish, mammals and plants (Ohshima et al., 1996, Mel. Cell. Biol., 16, 3756-3764; Okada and Hamada, 1997, J. Mol. Evol. 44, Suppl 1:S52-S56). In this review, we discuss the generality of this architecture of SINEs, adding new examples of pairs of SINEs and LINEs, which include one complete and two probable examples from this laboratory and one complete example from the laboratory of Arian Smit. This organization of SINEs and LINEs provides the basis for a simple general scheme by which SINEs might acquire retropositional activity. (C) 1997 Elsevier Science B.V.

DOI： 10.1016/S0378-1119(97)00409-5

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PubMed

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

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記述言語：英語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：英語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2011.07.1283

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2010.07.2477

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：英語   出版者・発行元：(一社)日本てんかん学会  

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記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

DOI： 10.1016/j.neures.2009.09.1434

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記述言語：日本語   出版者・発行元：日本てんかん学会  

CiNii Books

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記述言語：日本語   出版者・発行元：日本てんかん学会  

CiNii Books

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

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記述言語：日本語   出版者・発行元：日本てんかん学会  

CiNii Books

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記述言語：日本語   出版者・発行元：(一社)日本てんかん学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

てんかん責任遺伝子の同定は遺伝子診断法の確立だけでなく、てんかんの分子発症機序の理解と治療法の改良や開発に寄与すると期待されている。特に特発性てんかんは遺伝的素因があるものが多いと考えられていて、これまでに18遺伝子が責任遺伝子として同定されている。さらに、てんかん原因遺伝子に変異を持つ遺伝子操作マウスが作製され、個体、組織、細胞レベルでのてんかん発症機構の解明が進んでいる。一方、てんかん責任遺伝子の同定が進むにつれて、一つの遺伝子が複数のてんかんの責任遺伝子である場合や、同じてんかんに多数の責任遺伝子が存在する場合が判明し、責任遺伝子の同定を難しくしている。本章では特発性てんかん(一部の潜因性てんかんを含む)で同定された責任遺伝子、特にイオンチャネル遺伝子について概説する。(著者抄録)

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

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記述言語：日本語   出版者・発行元：日本てんかん学会  

CiNii Books

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER IRELAND LTD  

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記述言語：英語   出版者・発行元：日本神経化学会  

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記述言語：日本語  

CiNii Books

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記述言語：日本語  

J-GLOBAL

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語  

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記述言語：英語  

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