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Miriam H Meisler - One of the best experts on this subject based on the ideXlab platform.

  • Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.
    Human Mutation, 2018
    Co-Authors: Jacy L. Wagnon, Eric R. Wengert, Bryan S. Barker, Manoj K. Patel, Niccolo E. Mencacci, Kailash P. Bhatia, Bettina Balint, Miryam Carecchio, Nicholas W. Wood, Miriam H Meisler
    Abstract:

    Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron-derived cells demonstrated greatly reduced Nav 1.6 channel activity without altered gating properties. Hypomorphic alleles of SCN8A in the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures.

  • aberrant sodium channel currents and hyperexcitability of medial entorhinal cortex neurons in a mouse model of SCN8A encephalopathy
    The Journal of Neuroscience, 2017
    Co-Authors: Matteo Ottolini, Miriam H Meisler, Bryan S. Barker, Ronald P A Gaykema, Manoj K. Patel
    Abstract:

    SCN8A encephalopathy, or early infantile epileptic encephalopathy 13 (EIEE13), is caused predominantly by de novo gain-of-function mutations in the voltage-gated Na channel Nav1.6. Affected individuals suffer from refractory seizures, developmental delay, cognitive disability, and elevated risk of sudden unexpected death in epilepsy (SUDEP). A knock-in mouse model carrying the patient mutation p.Asn1768Asp (N1768D) reproduces many features of the disorder, including spontaneous seizures and SUDEP. We used the mouse model to examine the effects of the mutation on layer II stellate neurons of the medial entorhinal cortex (mEC), which transmit excitatory input to the hippocampus. Heterozygous (SCN8AD/+), homozygous (SCN8AD/D)), and WT (SCN8A+/+) littermates were compared at 3 weeks of age, the time of seizure onset for homozygous mice. Heterozygotes remain seizure free for another month. mEC layer II neurons of heterozygous and homozygous mice were hyperexcitable and generated long-lasting depolarizing potentials with bursts of action potentials after synaptic stimulation. Recording of Na currents revealed proexcitatory increases in persistent and resurgent currents and rightward shifts in inactivation parameters, leading to significant increases in the magnitude of window currents. The proexcitatory changes were more pronounced in homozygous mice than in heterozygotes, consistent with the earlier age of seizure onset in homozygotes. These studies demonstrate that the N1768D mutation increases the excitability of mEC layer II neurons by increasing persistent and resurgent Na currents and disrupting channel inactivation. The aberrant activities of mEC layer II neurons would provide excessive excitatory input to the hippocampus and contribute to hyperexcitability of hippocampal neurons in this model of SCN8A encephalopathy.SIGNIFICANCE STATEMENTSCN8A encephalopathy is a devastating neurological disorder that results from de novo mutations in the Na channel Nav1.6. In addition to seizures, patients suffer from cognitive and developmental delays and are at high risk for sudden unexpected death in epilepsy (SUDEP). A mouse knock-in model expressing the patient mutation N1768D reproduces several pathological phenotypes, including spontaneous seizures and sudden death. We demonstrate that medial entorhinal cortex (mEC) neurons from the mouse model exhibit proexcitatory alterations in Na channel activity, some of which were not seen in hippocampal or cortical neurons, and resulting in neuronal hyperexcitability. Because mEC neurons regulate the activity of the hippocampus, which plays an important role in seizure onset, we propose that these profound changes in mEC neuron excitability associated with the gain-of-function mutation of Nav1.6 may increase excitatory drive into the hippocampus, culminating in seizure activity and SUDEP.

  • Mutations of Sodium Channel SCN8A (Nav1.6) in Neurological Disease
    Ion Channels in Health and Disease, 2016
    Co-Authors: Jacy L. Wagnon, Rosie K. A. Bunton-stasyshyn, Miriam H Meisler
    Abstract:

    Abstract The voltage-gated sodium channel Na v 1.6, encoded by the SCN8A gene, is one of the most abundant sodium channels in human brain. In the axon initial segment of neurons, Na v 1.6 regulates the initiation of action potentials, and at nodes of Ranvier it contributes to nerve conduction velocity. Complete loss of SCN8A in the mouse results in paralysis due to failure of the neuromuscular junction, while partial loss-of-function mutations result in gait disorders, ataxia, and dystonia. The role of SCN8A in epilepsy has been recently revealed by large-scale exome sequencing. De novo missense mutations of SCN8A account for approximately 1% of cases of early infantile epileptic encephalopathy, designated EIEE13 (OMIM #614558). Heterozygous null mutations of SCN8A mutations can also result in isolated cognitive impairment. In cardiac myocytes, Na v 1.6 is localized to the transverse tubules where it functions in excitation–contraction coupling. Cardiac arrhythmias in patients with EIEE13 may contribute to sudden death (sudden unexpected death in epilepsy). The biophysical and pathogenic effects of missense mutations of SCN8A are being studied in transfected cells and knock-in mouse models. The emerging information suggests that mutations causing hyperactivity of Na v 1.6 result in epileptic encephalopathy, while loss-of-function mutations contribute to cognitive impairment and anxiety, and perhaps to psychiatric disease.

  • The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin.
    Epilepsia, 2016
    Co-Authors: Bryan S. Barker, Miriam H Meisler, Jacy L. Wagnon, Matteo Ottolini, Rachel M. Hollander, Manoj K. Patel
    Abstract:

    SummaryObjective SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0 and 18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin. Methods The mutation was introduced into the SCN8A cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μm) on mutant and wild-type (WT) channels were compared. Results Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, whereas inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μm) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use-dependent block of I1327V mutant channels relative to WT. Significance SCN8A – I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain-of-function mutations of SCN8A.

  • SCN8A encephalopathy: Research progress and prospects.
    Epilepsia, 2016
    Co-Authors: Miriam H Meisler, Shinichi Hirose, Alan L. Goldin, Guy Helman, Michael F. Hammer, Brandy E. Fureman, William D. Gaillard, Atsushi Ishii, Barbara L. Kroner, Christoph Lossin
    Abstract:

    On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care.

Jennifer A Kearney - One of the best experts on this subject based on the ideXlab platform.

  • scn3a deficiency associated with increased seizure susceptibility
    Neurobiology of Disease, 2017
    Co-Authors: Tyra Lamar, Andrew Escayg, Jennifer C Wong, Stacey B B Dutton, Benjamin S Jorge, Milen Velinov, Jeffrey D Calhoun, Carlos G. Vanoye, Jennifer A Kearney
    Abstract:

    Abstract Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.

  • novel scn3a variants associated with focal epilepsy in children
    Neurobiology of Disease, 2014
    Co-Authors: Carlos G. Vanoye, Katherine D Holland, Christina A Gurnett, Alfred L George, Jennifer A Kearney
    Abstract:

    Voltage-gated sodium (NaV) channels are essential for initiating and propagating action potentials in the brain. More than 800 mutations in genes encoding neuronal NaV channels including SCN1A and SCN2A have been associated with human epilepsy. Only one epilepsy-associated mutation has been identified in SCN3A encoding the NaV1.3 neuronal sodium channel. We performed a genetic screen of pediatric patients with focal epilepsy of unknown cause and identified four novel SCN3A missense variants: R357Q, D766N, E1111K and M1323V. We determined the functional consequences of these variants along with the previously reported K354Q mutation using heterologously expressed human NaV1.3. Functional defects were heterogeneous among the variants. The most severely affected was R357Q, which had a significantly smaller current density and slower activation than the wild-type (WT) channel as well as depolarized voltage dependences of activation and inactivation. Also notable was E1111K, which evoked a significantly greater level of persistent sodium current than WT channels. Interestingly, a common feature shared by all variant channels was increased current activation in response to depolarizing voltage ramps revealing a functional property consistent with conferring neuronal hyper-excitability. Discovery of a common biophysical defect among variants identified in unrelated pediatric epilepsy patients suggests that SCN3A may contribute to neuronal hyperexcitability and epilepsy.

  • mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
    Neuroscience Letters, 2008
    Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q alters an evolutionarily conserved amino acid in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.

  • mutation of sodium channel scn3a in a patient with cryptogenic pediatric partial epilepsy
    Neuroscience Letters, 2008
    Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for epilepsy. We screened a consecutive cohort of 18 children with cryptogenic partial epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood epilepsy.

  • impaired motor function in mice with cell specific knockout of sodium channel SCN8A nav1 6 in cerebellar purkinje neurons and granule cells
    Journal of Neurophysiology, 2006
    Co-Authors: Stephen I Levin, Zayd M Khaliq, Tina M Grieco, Teresa K Aman, Indira M Raman, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    The SCN8A gene encodes the voltage-gated Na channel α subunit NaV1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate SCN8A in all cells result in seve...

Andrew Escayg - One of the best experts on this subject based on the ideXlab platform.

  • Mutations in the SCN8A DIIS4 voltage sensor reveal new distinctions among hypomorphic and null Na v 1.6 sodium channels
    Genes Brain and Behavior, 2019
    Co-Authors: George Andrew S. Inglis, Jennifer C Wong, Kameryn M. Butler, Jacquelyn T. Thelin, Olivia C Mistretta, Xi Lin, Arthur W. English, Andrew Escayg
    Abstract:

    Mutations in the voltage-gated sodium channel gene SCN8A cause a broad range of human diseases, including epilepsy, intellectual disability, and ataxia. Here we describe three mouse lines on the C57BL/6J background with novel, overlapping mutations in the SCN8A DIIS4 voltage sensor: an in-frame 9 bp deletion (Δ9), an in-frame 3 bp insertion (∇3) and a 35 bp deletion that results in a frameshift and the generation of a null allele (Δ35). SCN8A Δ9/+ and SCN8A ∇3/+ heterozygous mutants display subtle motor deficits, reduced acoustic startle response, and are resistant to induced seizures, suggesting that these mutations reduce activity of the SCN8A channel protein, Nav 1.6. Heterozygous SCN8A Δ35/+ mutants show no alterations in motor function or acoustic startle response, but are resistant to induced seizures. Homozygous mutants from each line exhibit premature lethality and severe motor impairments, ranging from uncoordinated gait with tremor (Δ9 and ∇3) to loss of hindlimb control (Δ35). SCN8A Δ9/Δ9 and SCN8A ∇3/∇3 homozygous mutants also exhibit impaired nerve conduction velocity, while normal nerve conduction was observed in SCN8A Δ35/Δ35 homozygous mice. Our results suggest that hypomorphic mutations that reduce Nav 1.6 activity will likely result in different clinical phenotypes compared to null alleles. These three mouse lines represent a valuable opportunity to examine the phenotypic impacts of hypomorphic and null SCN8A mutations without the confound of strain-specific differences.

  • Selective targeting of SCN8A prevents seizure development in a mouse model of mesial temporal lobe epilepsy
    Scientific Reports, 2018
    Co-Authors: Jennifer C Wong, Tyra Lamar, Christopher D. Makinson, Qi Cheng, Jeffrey C. Wingard, Ernest F. Terwilliger, Andrew Escayg
    Abstract:

    We previously found that genetic mutants with reduced expression or activity of SCN8A are resistant to induced seizures and that co-segregation of a mutant SCN8A allele can increase survival and seizure resistance of Scn1a mutant mice. In contrast, SCN8A expression is increased in the hippocampus following status epilepticus and amygdala kindling. These findings point to SCN8A as a promising therapeutic target for epilepsy and raise the possibility that aberrant overexpression of SCN8A in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy. Using a small-hairpin-interfering RNA directed against the SCN8A gene, we selectively reduced SCN8A expression in the hippocampus of the intrahippocampal kainic acid (KA) mouse model of mesial temporal lobe epilepsy. We found that SCN8A knockdown prevented the development of spontaneous seizures in 9/10 mice, ameliorated KA-induced hyperactivity, and reduced reactive gliosis. These results support the potential of selectively targeting SCN8A for the treatment of refractory epilepsy.

  • scn3a deficiency associated with increased seizure susceptibility
    Neurobiology of Disease, 2017
    Co-Authors: Tyra Lamar, Andrew Escayg, Jennifer C Wong, Stacey B B Dutton, Benjamin S Jorge, Milen Velinov, Jeffrey D Calhoun, Carlos G. Vanoye, Jennifer A Kearney
    Abstract:

    Abstract Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.

  • De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis
    Epilepsy Research, 2016
    Co-Authors: Kameryn M. Butler, Cristina Da Silva, Yuval Shafir, James D. Weisfeld-adams, John J. Alexander, Madhuri Hegde, Andrew Escayg
    Abstract:

    Abstract Objectives To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. Methods Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A . Two additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. Results Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo , one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Na v 1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. Conclusions Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.

  • An Scn1a epilepsy mutation in SCN8A alters seizure susceptibility and behavior
    Experimental Neurology, 2015
    Co-Authors: Christopher D. Makinson, Ligia A. Papale, Alan L. Goldin, Karoni Dutt, Frank G. Lin, Anupama Shankar, Arthur J. Barela, Robert C. Liu, Andrew Escayg
    Abstract:

    Understanding the role of SCN8A in epilepsy and behavior is critical in light of recently identified human SCN8A epilepsy mutations. We have previously demonstrated that SCN8A(med) and SCN8A(med-jo) mice carrying mutations in the SCN8A gene display increased resistance to flurothyl and kainic acid-induced seizures; however, they also exhibit spontaneous absence seizures. To further investigate the relationship between altered SCN8A function and epilepsy, we introduced the SCN1A-R1648H mutation, identified in a family with generalized epilepsy with febrile seizures plus (GEFS+), into the corresponding position (R1627H) of the mouse SCN8A gene. Heterozygous R1627H mice exhibited increased resistance to some forms of pharmacologically and electrically induced seizures and the mutant SCN8A allele ameliorated the phenotype of Scn1a-R1648H mutants. Hippocampal slices from heterozygous R1627H mice displayed decreased bursting behavior compared to wild-type littermates. Paradoxically, at the homozygous level, R1627H mice did not display increased seizure resistance and were susceptible to audiogenic seizures. We furthermore observed increased hippocampal pyramidal cell excitability in heterozygous and homozygous SCN8A-R1627H mutants, and decreased interneuron excitability in heterozygous SCN8A-R1627H mutants. These results expand the phenotypes associated with disruption of the SCN8A gene and demonstrate that an SCN8A mutation can both confer seizure protection and increase seizure susceptibility.

Stephen I Levin - One of the best experts on this subject based on the ideXlab platform.

  • impaired motor function in mice with cell specific knockout of sodium channel SCN8A nav1 6 in cerebellar purkinje neurons and granule cells
    Journal of Neurophysiology, 2006
    Co-Authors: Stephen I Levin, Zayd M Khaliq, Tina M Grieco, Teresa K Aman, Indira M Raman, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    The SCN8A gene encodes the voltage-gated Na channel α subunit NaV1.6, which is widely expressed throughout the nervous system. Global null mutations that eliminate SCN8A in all cells result in seve...

  • Inactivation of sodium channel SCN8A (Na-sub(v)1.6) in Purkinje neurons impairs learning in Morris water maze and delay but not trace eyeblink classical conditioning.
    Behavioral Neuroscience, 2006
    Co-Authors: Diana S. Woodruff-pak, Stephen I Levin, John T. Green, Miriam H Meisler
    Abstract:

    To examine the isolated effects of altered currents in cerebellar Purkinje neurons, the authors used SCN8A-super(flox/flox), Purkinje cell protein-CRE (Pcp-CRE) mice in which Exon 1 of SCN8A is deleted only in Purkinje neurons. Twenty male Purkinje SCN8A knockout (PKJ SCN8A KO) mice and 20 male littermates were tested on the Morris water maze (MWM). Subsequently, half were tested in 500-ms delay and half were tested in 500-ms trace eyeblink conditioning. PKJ SCN8A KO mice were impaired in delay conditioning and MWM but not in trace conditioning. These results provide additional support for the necessary participation of cerebellar cortex in normal acquisition of delay eyeblink conditioning and MWM and raise questions about the role, if any, of cerebellar cortex in trace eyeblink conditioning.

  • floxed allele for conditional inactivation of the voltage gated sodium channel SCN8A nav1 6
    Genesis, 2004
    Co-Authors: Stephen I Levin, Miriam H Meisler
    Abstract:

    The sodium channel gene SCN8A encodes the channel NaV1.6, which is widely distributed in the central and peripheral nervous system. NaV1.6 is the major channel at the nodes of Ranvier in myelinated axons. Mutant alleles of mouse SCN8A result in neurological disorders including ataxia, tremor, paralysis, and dystonia. We generated a floxed allele of SCN8A by inserting loxP sites around the first coding exon. The initial targeted allele containing the neo-cassette was a severe hypomorph. In vivo deletion of the neo-cassette by Flp recombinase produced a floxed allele that generates normal expression of NaV1.6 protein. Ubiquitous deletion of the floxed exon by Cre recombinase in ZP3-Cre transgenic mice produced the SCN8Adel allele. The null phenotype of SCN8Adel homozygotes confirms the in vivo inactivation of SCN8A. Conditional inactivation of the floxed allele will make it possible to circumvent the lethality that results from complete loss of SCN8A in order to investigate the physiologic role of NaV1.6 in subpopulations of neurons. genesis 39:234–239, 2004. © 2004 Wiley-Liss, Inc.

  • Floxed allele for conditional inactivation of the voltage‐gated sodium channel SCN8A (Nav1.6)
    Genesis, 2004
    Co-Authors: Stephen I Levin, Miriam H Meisler
    Abstract:

    The sodium channel gene SCN8A encodes the channel NaV1.6, which is widely distributed in the central and peripheral nervous system. NaV1.6 is the major channel at the nodes of Ranvier in myelinated axons. Mutant alleles of mouse SCN8A result in neurological disorders including ataxia, tremor, paralysis, and dystonia. We generated a floxed allele of SCN8A by inserting loxP sites around the first coding exon. The initial targeted allele containing the neo-cassette was a severe hypomorph. In vivo deletion of the neo-cassette by Flp recombinase produced a floxed allele that generates normal expression of NaV1.6 protein. Ubiquitous deletion of the floxed exon by Cre recombinase in ZP3-Cre transgenic mice produced the SCN8Adel allele. The null phenotype of SCN8Adel homozygotes confirms the in vivo inactivation of SCN8A. Conditional inactivation of the floxed allele will make it possible to circumvent the lethality that results from complete loss of SCN8A in order to investigate the physiologic role of NaV1.6 in subpopulations of neurons. genesis 39:234–239, 2004. © 2004 Wiley-Liss, Inc.

Larry Baum - One of the best experts on this subject based on the ideXlab platform.

  • case control association study of polymorphisms in the voltage gated sodium channel genes scn1a scn2a scn3a scn1b and scn2b and epilepsy
    Human Genetics, 2014
    Co-Authors: Larry Baum, Batoul Sadat Haerian, Ping Wing Ng, Gary Wingkin Wong, Brian Tomlinson, Virginia Wong, Ho Keung Ng, Chunbo Zhang, A. A. Raymond, Zahurin Mohamed
    Abstract:

    High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r 2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.

  • Case–control association study of polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B and epilepsy
    Human Genetics, 2013
    Co-Authors: Larry Baum, Batoul Sadat Haerian, Ping Wing Ng, Brian Tomlinson, Virginia Wong, Ho Keung Ng, Chunbo Zhang, Gary Wingkin Wong
    Abstract:

    High-frequency action potentials are mediated by voltage-gated sodium channels, composed of one large α subunit and two small β subunits, encoded mainly by SCN1A, SCN2A, SCN3A, SCN1B, and SCN2B genes in the brain. These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A. We examined whether polymorphisms in the above genes affect epilepsy risk in 1,529 epilepsy patients and 1,935 controls from four ethnicities or locations: Malay, Indian, and Chinese, all from Malaysia, and Chinese from Hong Kong. Of patients, 19 % were idiopathic, 42 % symptomatic, and 40 % cryptogenic. We genotyped 43 polymorphisms: 27 in Hong Kong, 28 in Malaysia, and 12 in both locations. The strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A: odds ratio (OR) = 0.85 for allele G (p = 0.0009) and 0.73 for genotype GG versus AA (p = 0.003). The OR was between 0.76 and 0.87 for all ethnicities. Meta-analysis confirmed the association (OR = 0.81 and p = 0.002 for G, and OR = 0.67 and p = 0.007 for GG versus AA), which appeared particularly strong for Indians and for febrile seizures. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r 2 = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy.

  • scn1a scn2a and scn3a gene polymorphisms and responsiveness to antiepileptic drugs a multicenter cohort study and meta analysis
    Pharmacogenomics, 2013
    Co-Authors: Batoul Sadat Haerian, Larry Baum, Patrick Kwan, A. A. Raymond, Zahurin Mohamed
    Abstract:

    Aim: Approximately a third of newly diagnosed epilepsy patients do not respond to antiepileptic drugs (AEDs). Evidence suggests that low penetrance variants in the genes of drug targets such as voltage-gated sodium channels may be involved in drug responsiveness. To examine this hypothesis, we compared data from two epilepsy cohorts from Malaysia and Hong Kong, as well as a meta-analysis from published data. Materials & methods: Genotype analysis of 39 polymorphisms located in the SCN1A, SCN2A and SCN3A genes was performed on 1504 epilepsy patients from Malaysia and Hong Kong who were receiving AEDs. Meta-analysis was performed for pooled data of SCN1A rs3812718 and rs2298771, and SCN2A rs17183814 polymorphisms. Results: Our data from the Hong Kong and Malaysia cohorts showed no significant allele, genotype and haplotype association of polymorphisms in the SCN1A, SCN2A, and SCN3A genes with drug responsiveness in epilepsy. This finding was supported by a meta-analysis for SCN1A rs3812718 and rs2298771, an...

  • multidrug resistance in epilepsy and polymorphisms in the voltage gated sodium channel genes scn1a scn2a and scn3a correlation among phenotype genotype and mrna expression
    Pharmacogenetics and Genomics, 2008
    Co-Authors: Patrick Kwan, Ping Wing Ng, David E Kang, Ka S Wong, Virginia Wong, Ho Keung Ng, Wai Sang Poon, Larry Baum
    Abstract:

    ObjectivesMany antiepileptic drugs (AEDs) prevent seizures by blocking voltage-gated brain sodium channels. However, treatment is ineffective in 30% of epilepsy patients, which might, at least in part, result from polymorphisms of the sodium channel genes. We investigated the association of AED resp