The Experts below are selected from a list of 675 Experts worldwide ranked by ideXlab platform
Jennifer A Kearney - One of the best experts on this subject based on the ideXlab platform.
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SCN3A deficiency associated with increased seizure susceptibility
Neurobiology of Disease, 2017Co-Authors: Tyra Lamar, Andrew Escayg, Carlos G Vanoye, Jeffrey D Calhoun, Jennifer C Wong, Stacey B B Dutton, Benjamin S Jorge, Milen Velinov, Jennifer A KearneyAbstract: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.
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novel SCN3A variants associated with focal epilepsy in children
Neurobiology of Disease, 2014Co-Authors: Carlos G Vanoye, Katherine D Holland, Christina A Gurnett, Alfred L George, Jennifer A KearneyAbstract: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.
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Fine mapping of an epilepsy modifier gene on mouse Chromosome 19
Mammalian Genome, 2009Co-Authors: Sarah K. Bergren, Elizabeth D. Rutter, Jennifer A KearneyAbstract:Mutations in voltage-gated sodium channels are associated with several types of human epilepsy. Variable expressivity and penetrance are common features of inherited epilepsy caused by sodium channel mutations, suggesting that genetic modifiers may influence clinical severity. The mouse model Scn2a ^ Q54 has an epilepsy phenotype due to a mutation in Scn2a that results in elevated persistent sodium current. Phenotype severity in Scn2a ^ Q54 mice is dependent on the genetic background. Congenic C57BL/6J.Q54 mice have delayed onset and low seizure frequency compared to (C57BL/6J × SJL/J)F1.Q54 mice. Previously, we identified two modifier loci that influence the Scn2a ^ Q54 epilepsy phenotype: Moe1 ( m odifier o f e pilepsy 1) on Chromosome 11 and Moe2 on Chromosome 19. We have constructed interval-specific congenic strains to further refine the position of Moe2 on Chromosome 19 to a 5-Mb region. Sequencing and expression analyses of genes in the critical interval suggested two potential modifier candidates: (1) voltage-gated potassium channel subunit subfamily V, member 2 ( Kcnv2 ), and (2) SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2 ( Smarca2 ). Based on its biological role in regulating membrane excitability and the association between ion channel variants and seizures, Kcnv2 is a strong functional candidate for Moe2 . Modifier genes affecting the epilepsy phenotype of Scn2a ^ Q54 mice may contribute to variable expressivity and penetrance in human epilepsy patients with sodium channel mutations.
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mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Jennifer A Kearney, Tracy A Glauser, Gerri Buck, Mehdi Keddache, John R Blankston, Ian W Glaaser, Robert S Kass, Miriam H MeislerAbstract: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.
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mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Jennifer A Kearney, Tracy A Glauser, Gerri Buck, Mehdi Keddache, John R Blankston, Ian W Glaaser, Robert S Kass, Miriam H MeislerAbstract: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.
Miriam H Meisler - One of the best experts on this subject based on the ideXlab platform.
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Sodium channel gene family: epilepsy mutations, gene interactions and modifier effects.
The Journal of physiology, 2010Co-Authors: Miriam H Meisler, Janelle E O'brien, Lisa M SharkeyAbstract:The human sodium channel family includes seven neuronal channels that are essential for the initiation and propagation of action potentials in the CNS and PNS. In view of their critical role in neuronal firing and their strong sequence conservation during evolution, it is not surprising that mutations in the sodium channel genes are responsible for a growing spectrum of channelopathies. Nearly 700 mutations of the SCN1A gene have been identified in patients with Dravet's syndrome (severe myoclonic epilepsy of infancy), making this the most commonly mutated gene in human epilepsy. A small number of mutations have been found in SCN2A, SCN3A and SCN9A, and studies in the mouse suggest that SCN8A may also contribute to seizure disorders. Interactions between genetic variants of SCN2A and KCNQ2 in the mouse and variants of SCN1A and SCN9A in patients provide models of potential genetic modifier effects in the more common human polygenic epilepsies. New methods for generating induced pluripotent stem cells and neurons from patients will facilitate functional analysis of amino acid substitutions in channel proteins. Whole genome sequencing and exome sequencing in patients with epilepsy will soon make it possible to detect multiple variants and their interactions in the genomes of patients with seizure disorders.
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altered function of the scn1a voltage gated sodium channel leads to γ aminobutyric acid ergic gabaergic interneuron abnormalities
Journal of Biological Chemistry, 2010Co-Authors: Melinda S. Martin, Miriam H Meisler, Ligia A. Papale, Stacey B B Dutton, Karoni Dutt, Celine Dube, Georgius De Haan, Anupama Shankar, Sergio Tufik, Tallie Z BaramAbstract:Voltage-gated sodium channels are required for the initiation and propagation of action potentials. Mutations in the neuronal voltage-gated sodium channel SCN1A are associated with a growing number of disorders including generalized epilepsy with febrile seizures plus (GEFS+),(7) severe myoclonic epilepsy of infancy, and familial hemiplegic migraine. To gain insight into the effect of SCN1A mutations on neuronal excitability, we introduced the human GEFS+ mutation SCN1A-R1648H into the orthologous mouse gene. Scn1a(RH/RH) mice homozygous for the R1648H mutation exhibit spontaneous generalized seizures and premature death between P16 and P26, whereas Scn1a(RH/+) heterozygous mice exhibit infrequent spontaneous generalized seizures, reduced threshold and accelerated propagation of febrile seizures, and decreased threshold to flurothyl-induced seizures. Inhibitory cortical interneurons from P5-P15 Scn1a(RH/+) and Scn1a(RH/RH) mice demonstrated slower recovery from inactivation, greater use-dependent inactivation, and reduced action potential firing compared with wild-type cells. Excitatory cortical pyramidal neurons were mostly unaffected. These results suggest that this SCN1A mutation predominantly impairs sodium channel activity in interneurons, leading to decreased inhibition. Decreased inhibition may be a common mechanism underlying clinically distinct SCN1A-derived disorders.
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mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Jennifer A Kearney, Tracy A Glauser, Gerri Buck, Mehdi Keddache, John R Blankston, Ian W Glaaser, Robert S Kass, Miriam H MeislerAbstract: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.
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mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy
Neuroscience Letters, 2008Co-Authors: Katherine D Holland, Jennifer A Kearney, Tracy A Glauser, Gerri Buck, Mehdi Keddache, John R Blankston, Ian W Glaaser, Robert S Kass, Miriam H MeislerAbstract: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.
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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, 2006Co-Authors: Stephen I Levin, Jennifer A Kearney, Zayd M Khaliq, Teresa K Aman, Tina M Grieco, Indira M Raman, Miriam H MeislerAbstract: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...
Qihua Zhao - One of the best experts on this subject based on the ideXlab platform.
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epigenetic downregulation of SCN3A expression by valproate a possible role in its anticonvulsant activity
Molecular Neurobiology, 2017Co-Authors: Ping Lu, Huiling Tang, Yonghong Chen, Qihua Zhao, Haijun LiAbstract:Upregulation of sodium channel SCN3A expression in epileptic tissues is known to contribute to enhancing neuronal excitability and the development of epilepsy. Therefore, certain strategies to reduce SCN3A expression may be helpful for seizure control. Here, we reveal a novel role of valproate (VPA) in the epigenetic downregulation of SCN3A expression. We found that VPA, instead of carbamazepine (CBZ) and lamotrigine (LTG), could significantly downregulate SCN3A expression in mouse Neuro-2a cells. Luciferase assays and CpG methylation analyses showed that VPA induced the methylation at the -39C site in SCN3A promoter which decreased the promoter activity. We further showed that VPA downregulated the expression of methyl-CpG-binding domain protein 2 (MBD2) at the posttranscriptional level and knockdown of MBD2 increased SCN3A expression. In addition, we found that VPA induced the expression of fat mass and obesity-associated (FTO) protein and FTO knockdown abolished the repressive effects of VPA on MBD2 and Nav1.3 expressions. Furthermore, VPA, instead of other two anticonvulsant drugs, induced the expressions of SCN3A and Mbd2 and reduced Fto expression in the hippocampus of VPA-treated seizure mice. Taken together, this study suggests an epigenetic pathway for the VPA-induced downregulation of SCN3A expression, which provides a possible role of this pathway in the anticonvulsant action of VPA.
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gapdh mediated posttranscriptional regulations of sodium channel scn1a and SCN3A genes under seizure and ketogenic diet conditions
Neuropharmacology, 2017Co-Authors: Ping Lu, Tao Zeng, Huiling Tang, Yonghong Chen, Qihua Zhao, Yonghong Yi, Yuesheng LongAbstract:Abstract Abnormal expressions of sodium channel SCN1A and SCN3A genes alter neural excitability that are believed to contribute to the pathogenesis of epilepsy, a long-term risk of recurrent seizures. Ketogenic diet (KD), a high-fat and low-carbohydrate treatment for difficult-to-control (refractory) epilepsy in children, has been suggested to reverse gene expression patterns. Here, we reveal a novel role of GAPDH on the posttranscriptional regulation of mouse Scn1a and SCN3A expressions under seizure and KD conditions. We show that GAPDH binds to a conserved region in the 3′ UTRs of human and mouse SCN1A and SCN3A genes, which decreases and increases genes' expressions by affecting mRNA stability through SCN1A 3′ UTR and SCN3A 3′ UTR, respectively. In seizure mice, the upregulation and phosphorylation of GAPDH enhance its binding to the 3′ UTR, which lead to downregulation of Scn1a and upregulation of SCN3A. Furthermore, administration of KD generates β-hydroxybutyric acid which rescues the abnormal expressions of Scn1a and SCN3A by weakening the GAPDH's binding to the element. Taken together, these data suggest that GAPDH-mediated expression regulation of sodium channel genes may be associated with epilepsy and the anticonvulsant action of KD.
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alteration of SCN3A expression is mediated via cpg methylation and mbd2 in mouse hippocampus during postnatal development and seizure condition
Biochimica et Biophysica Acta, 2015Co-Authors: Weiping Liao, Qihua Zhao, Yonghong Yi, Haijun Li, Lingjia Tang, Yuesheng LongAbstract:Increased expression of sodium channel SCN3A, an embryonic-expressed gene, has been identified in epileptic tissues, which is believed to contribute to the development of epilepsy. However, the regulatory mechanism of SCN3A expression under epileptic condition is still unknown. Here we showed a high level of SCN3A mRNA expression in mouse embryonic hippocampus with gradually decreasing to a low level during the postnatal development and a methylation of a specific CpG site (-39C) in the SCN3A promoter was increased in hippocampus during postnatal development, corresponding to the downregulation of SCN3A expression. Furthermore, in vitro methylation and -39C>T mutation of the SCN3A promoter decreased the reporter gene expression, suggesting an important role of the -39C site in regulating gene expression. We then demonstrated that the sequence containing -39C was a MBD2-binding motif and the CpG methylation of the promoter region increased the capability of MBD2's binding to the motif. Knockdown of MBD2 in mouse N1E-115 cells led to the -39C methylation and the downregulation of SCN3A transcription by decreasing the SCN3A promoter activity. In the hippocampus of seizure mice, the expressions of SCN3A and Mbd2 were upregulated after 10-day KA treatment. At the same time point, the -39C site was demethylated and the capability of MBD2's binding to the SCN3A promoter motif was decreased. Taken together, these findings suggest that CpG methylation and MBD2 are involved in altering SCN3A expression during postnatal development and seizure condition.
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promoter analysis of mouse SCN3A gene and regulation of the promoter activity by gc box and cpg methylation
Journal of Molecular Neuroscience, 2011Co-Authors: Guangfei Deng, Weiping Liao, Qihua Zhao, Yonghong Yi, Zuying Kuang, Tao Su, Meijuan Yu, Yuesheng LongAbstract:Voltage-gated sodium channel α-subunit type III (Nav1.3) is mainly expressed in the central nervous system and is associated with neurological disorders. The expression of mouse SCN3A product (Nav1.3) mainly occurs in embryonic and early postnatal brain but not in adult brain. Here, we report for the first time the identification and characterization of the mouse SCN3A gene promoter region and regulation of the promoter activity by GC box and CpG methylation. Luciferase assay showed that the promoter region F1.2 (nt −1,049 to +157) had significantly higher activity in PC12 cells, comparing with that in SH-SY5Y cells and HEK293 cells. A stepwise 5′ truncation of the promoter region found that the minimal functional promoter located within the region nt −168 to +157. Deletion of a GC box (nt −254 to −258) in the mouse SCN3A promoter decreased the promoter activity. CpG methylation of the F1.2 without the GC box completely repressed the promoter activity, suggesting that the GC box is a critical element in the CpG-methylated SCN3A promoter. These results suggest that the GC box and CpG methylation might play important roles in regulating mouse SCN3A gene expression.
Yuesheng Long - One of the best experts on this subject based on the ideXlab platform.
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gapdh mediated posttranscriptional regulations of sodium channel scn1a and SCN3A genes under seizure and ketogenic diet conditions
Neuropharmacology, 2017Co-Authors: Ping Lu, Tao Zeng, Huiling Tang, Yonghong Chen, Qihua Zhao, Yonghong Yi, Yuesheng LongAbstract:Abstract Abnormal expressions of sodium channel SCN1A and SCN3A genes alter neural excitability that are believed to contribute to the pathogenesis of epilepsy, a long-term risk of recurrent seizures. Ketogenic diet (KD), a high-fat and low-carbohydrate treatment for difficult-to-control (refractory) epilepsy in children, has been suggested to reverse gene expression patterns. Here, we reveal a novel role of GAPDH on the posttranscriptional regulation of mouse Scn1a and SCN3A expressions under seizure and KD conditions. We show that GAPDH binds to a conserved region in the 3′ UTRs of human and mouse SCN1A and SCN3A genes, which decreases and increases genes' expressions by affecting mRNA stability through SCN1A 3′ UTR and SCN3A 3′ UTR, respectively. In seizure mice, the upregulation and phosphorylation of GAPDH enhance its binding to the 3′ UTR, which lead to downregulation of Scn1a and upregulation of SCN3A. Furthermore, administration of KD generates β-hydroxybutyric acid which rescues the abnormal expressions of Scn1a and SCN3A by weakening the GAPDH's binding to the element. Taken together, these data suggest that GAPDH-mediated expression regulation of sodium channel genes may be associated with epilepsy and the anticonvulsant action of KD.
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alteration of SCN3A expression is mediated via cpg methylation and mbd2 in mouse hippocampus during postnatal development and seizure condition
Biochimica et Biophysica Acta, 2015Co-Authors: Weiping Liao, Qihua Zhao, Yonghong Yi, Haijun Li, Lingjia Tang, Yuesheng LongAbstract:Increased expression of sodium channel SCN3A, an embryonic-expressed gene, has been identified in epileptic tissues, which is believed to contribute to the development of epilepsy. However, the regulatory mechanism of SCN3A expression under epileptic condition is still unknown. Here we showed a high level of SCN3A mRNA expression in mouse embryonic hippocampus with gradually decreasing to a low level during the postnatal development and a methylation of a specific CpG site (-39C) in the SCN3A promoter was increased in hippocampus during postnatal development, corresponding to the downregulation of SCN3A expression. Furthermore, in vitro methylation and -39C>T mutation of the SCN3A promoter decreased the reporter gene expression, suggesting an important role of the -39C site in regulating gene expression. We then demonstrated that the sequence containing -39C was a MBD2-binding motif and the CpG methylation of the promoter region increased the capability of MBD2's binding to the motif. Knockdown of MBD2 in mouse N1E-115 cells led to the -39C methylation and the downregulation of SCN3A transcription by decreasing the SCN3A promoter activity. In the hippocampus of seizure mice, the expressions of SCN3A and Mbd2 were upregulated after 10-day KA treatment. At the same time point, the -39C site was demethylated and the capability of MBD2's binding to the SCN3A promoter motif was decreased. Taken together, these findings suggest that CpG methylation and MBD2 are involved in altering SCN3A expression during postnatal development and seizure condition.
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promoter analysis of mouse SCN3A gene and regulation of the promoter activity by gc box and cpg methylation
Journal of Molecular Neuroscience, 2011Co-Authors: Guangfei Deng, Weiping Liao, Qihua Zhao, Yonghong Yi, Zuying Kuang, Tao Su, Meijuan Yu, Yuesheng LongAbstract:Voltage-gated sodium channel α-subunit type III (Nav1.3) is mainly expressed in the central nervous system and is associated with neurological disorders. The expression of mouse SCN3A product (Nav1.3) mainly occurs in embryonic and early postnatal brain but not in adult brain. Here, we report for the first time the identification and characterization of the mouse SCN3A gene promoter region and regulation of the promoter activity by GC box and CpG methylation. Luciferase assay showed that the promoter region F1.2 (nt −1,049 to +157) had significantly higher activity in PC12 cells, comparing with that in SH-SY5Y cells and HEK293 cells. A stepwise 5′ truncation of the promoter region found that the minimal functional promoter located within the region nt −168 to +157. Deletion of a GC box (nt −254 to −258) in the mouse SCN3A promoter decreased the promoter activity. CpG methylation of the F1.2 without the GC box completely repressed the promoter activity, suggesting that the GC box is a critical element in the CpG-methylated SCN3A promoter. These results suggest that the GC box and CpG methylation might play important roles in regulating mouse SCN3A gene expression.
Katherine L. Helbig - One of the best experts on this subject based on the ideXlab platform.
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mutations in SCN3A cause early infantile epileptic encephalopathy
Annals of Neurology, 2018Co-Authors: Tariq Zaman, Ingo Helbig, Suzanne D. Debrosse, A. G. Christina Bergqvist, Kimberly Wallis, Livija Medne, Ales Maver, Borut Peterlin, Ivana Babic Božovic, Katherine L. HelbigAbstract:OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala). METHODS: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria. RESULTS: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels. INTERPRETATION: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703-717.
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Mutations in SCN3A cause early infantile epileptic encephalopathy.
Annals of Neurology, 2018Co-Authors: Tariq Zaman, Ingo Helbig, Ivana Babić Božović, Suzanne D. Debrosse, A. G. Christina Bergqvist, Kimberly Wallis, Livija Medne, Ales Maver, Borut Peterlin, Katherine L. HelbigAbstract:Objective Voltage-gated sodium (Na+) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1, are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of four patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in two cases, p.Pro1333Leu, and p.Val1769Ala).