A Study among the Genotype, Functional Alternations, and Phenotype of 9 SCN1A Mutations in Epilepsy Patients.

Tytuł:: A Study among the Genotype, Functional Alternations, and Phenotype of 9 SCN1A Mutations in Epilepsy Patients.
Autorzy:: Kluckova D; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, 842 15, Slovakia.
Kolnikova M; Department of Pediatric Neurology, Comenius University Medical School and National Institute of Children's Diseases, Limbova 1, Bratislava, 833 40, Slovakia.
Lacinova L; Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dubravská cesta 9, Bratislava, 840 05, Slovakia.
Jurkovicova-Tarabova B; Center of Biosciences, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Dubravská cesta 9, Bratislava, 840 05, Slovakia.
Foltan T; Department of Pediatric Neurology, Comenius University Medical School and National Institute of Children's Diseases, Limbova 1, Bratislava, 833 40, Slovakia.
Demko V; Department of Plant Physiology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, 842 15, Slovakia.
Kadasi L; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, 842 15, Slovakia.; Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia.
Ficek A; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, 842 15, Slovakia.
Soltysova A; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, Bratislava, 842 15, Slovakia. .; Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia. .
Źródło:: Scientific reports [Sci Rep] 2020 Jun 24; Vol. 10 (1), pp. 10288. Date of Electronic Publication: 2020 Jun 24.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: London : Nature Publishing Group, copyright 2011-
MeSH Terms:: Epilepsy/*genetics
Membrane Potentials/*genetics
NAV1.1 Voltage-Gated Sodium Channel/*genetics
Adolescent ; Age of Onset ; Brain/diagnostic imaging ; Brain/physiopathology ; Child ; Child, Preschool ; DNA Mutational Analysis ; Diagnostic Errors/prevention & control ; Epilepsy/diagnosis ; Epilepsy/physiopathology ; Female ; Genetic Association Studies ; HEK293 Cells ; Humans ; Magnetic Resonance Imaging ; Male ; Mutagenesis ; Mutation ; NAV1.1 Voltage-Gated Sodium Channel/metabolism ; Patch-Clamp Techniques ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Sodium/metabolism ; Transfection
References:: Goldberg-Stern, H. et al. Broad phenotypic heterogeneity due to a novel SCN1A mutation in a family with genetic epilepsy with febrile seizures plus. J. Child Neurol. 29, 221–226, https://doi.org/10.1177/0883073813509016 (2014). (PMID: 10.1177/088307381350901624257433)
Passamonti, C. et al. A novel inherited SCN1A mutation associated with different neuropsychological phenotypes: Is there a common core deficit? Epilepsy Behav. 43, 89–92, https://doi.org/10.1016/j.yebeh.2014.11.009 (2015). (PMID: 10.1016/j.yebeh.2014.11.00925569746)
Scheffer, I. E., Zhang, Y.-H., Jansen, F. E. & Dibbens, L. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? Brain Dev. 31, 394–400, https://doi.org/10.1016/j.braindev.2009.01.001 (2009). (PMID: 10.1016/j.braindev.2009.01.00119203856)
Epi4 K & Investigators, E. De novo mutations in the classic epileptic encephalopathies. Nature 501, 217, https://doi.org/10.1038/nature12439 (2013).
Selmer, K. K., Lund, C., Brandal, K., Undlien, D. E. & Brodtkorb, E. SCN1A mutation screening in adult patients with Lennox–Gastaut syndrome features. Epilepsy Behav. 16, 555–557, https://doi.org/10.1016/j.yebeh.2009.08.021 (2009). (PMID: 10.1016/j.yebeh.2009.08.02119782004)
Harkin, L. A. et al. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 130, 843–852, https://doi.org/10.1093/brain/awm002 (2007). (PMID: 10.1093/brain/awm00217347258)
Zuberi, S. et al. Genotype–phenotype associations in SCN1A-related epilepsies. Neurology 76, 594–600, https://doi.org/10.1212/WNL.0b013e31820c309b (2011). (PMID: 10.1212/WNL.0b013e31820c309b21248271)
Carvill, G. L. et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 45, 825, https://doi.org/10.1038/ng.2646 (2013). (PMID: 10.1038/ng.2646237081873704157)
Wang, J. W. et al. Prevalence of SCN1A mutations in children with suspected Dravet syndrome and intractable childhood epilepsy. Epilepsy Res. 102, 195–200, https://doi.org/10.1016/j.eplepsyres.2012.06.006 (2012). (PMID: 10.1016/j.eplepsyres.2012.06.00623195492)
Wallace, R. et al. Sodium channel α1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms. Neurology 61, 765–769, https://doi.org/10.1212/01.WNL.0000086379.71183.78 (2003). (PMID: 10.1212/01.WNL.0000086379.71183.7814504318)
Weller, C. M. et al. Two novel SCN1A mutations identified in families with familial hemiplegic migraine. Cephalalgia 34, 1062–1069, https://doi.org/10.1177/0333102414529195 (2014). (PMID: 10.1177/033310241452919524707016)
Meng, H. et al. The SCN1A Mutation Database: Updating Information and Analysis of the Relationships among Genotype, Functional Alteration, and Phenotype. Hum. Mutat. 36, 573–580, https://doi.org/10.1002/humu.22782 (2015). (PMID: 10.1002/humu.2278225754450)
Claes, L. et al. De novo SCN1A mutations are a major cause of severe myoclonic epilepsy of infancy. Hum. Mutat. 21, 615–621, https://doi.org/10.1002/humu.10217 (2003). (PMID: 10.1002/humu.1021712754708)
Claes, L. et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68, 1327–1332, https://doi.org/10.1086/320609 (2001). (PMID: 10.1086/320609113592111226119)
Ohmori, I., Ouchida, M., Ohtsuka, Y., Oka, E. & Shimizu, K. Significant correlation of the SCN1A mutations and severe myoclonic epilepsy in infancy. Biochem. Biophys. Res. Commun. 295, 17–23, https://doi.org/10.1016/S0006-291X(02)00617-4 (2002). (PMID: 10.1016/S0006-291X(02)00617-412083760)
Ceulemans, B. P., Claes, L. R. & Lagae, L. G. Clinical correlations of mutations in the SCN1A gene: from febrile seizures to severe myoclonic epilepsy in infancy. Pediatr. Neurol. 30, 236–243, https://doi.org/10.1016/j.pediatrneurol.2003.10.012 (2004). (PMID: 10.1016/j.pediatrneurol.2003.10.01215087100)
Kanai, K. et al. Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity. Neurology 63, 329–334, https://doi.org/10.1212/01.WNL.0000129829.31179.5B (2004). (PMID: 10.1212/01.WNL.0000129829.31179.5B15277629)
Sadleir, L. G. et al. Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype. Neurology 89, 1035–1042, https://doi.org/10.1212/WNL.0000000000004331 (2017). (PMID: 10.1212/WNL.0000000000004331287942495589790)
Surovy, M. et al. Novel SCN1A variants in Dravet syndrome and evaluating a wide approach of patient selection. Gen. Physiol. Biophys. 35, 333–342, https://doi.org/10.4149/gpb_2016002 (2016). (PMID: 10.4149/gpb_201600227045673)
Mancardi, M. M. et al. Familial occurrence of febrile seizures and epilepsy in severe myoclonic epilepsy of infancy (SMEI) patients with SCN1A mutations. Epilepsia 47, 1629–1635, https://doi.org/10.1111/j.1528-1167.2006.00641.x (2006). (PMID: 10.1111/j.1528-1167.2006.00641.x17054684)
Depienne, C. et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J. Med. Genet. 46, 183–191, https://doi.org/10.1136/jmg.2008.062323 (2009). (PMID: 10.1136/jmg.2008.06232318930999)
Dlugos, D. J., Ferraro, T. N. & Buono, R. J. Novel de novo mutation of a conserved SCN1A amino-acid residue (R1596). Pediatr. Neurol. 37, 303–305, https://doi.org/10.1016/j.pediatrneurol.2007.06.008 (2007). (PMID: 10.1016/j.pediatrneurol.2007.06.00817903680)
Hoffman-Zacharska, D. et al. From focal epilepsy to Dravet syndrome–Heterogeneity of the phenotype due to SCN1A mutations of the p. Arg1596 amino acid residue in the Nav1. 1 subunit. Neurol. Neurochir. Pol. 49, 258–266, https://doi.org/10.1016/j.pjnns.2015.06.006 (2015). (PMID: 10.1016/j.pjnns.2015.06.00626188943)
Kim, Y. O. et al. Atypical multifocal Dravet syndrome lacks generalized seizures and may show later cognitive decline. Dev. Med. Child Neurol. 56, 85–90, https://doi.org/10.1111/dmcn.12322 (2014). (PMID: 10.1111/dmcn.1232224328833)
Nicita, F. et al. Genotype-phenotype correlations in a group of 15 SCN1A-mutated Italian patients with GEFS+ spectrum (seizures plus, classical and borderline severe myoclonic epilepsy of infancy). J. Child Neurol. 25, 1369–1376, https://doi.org/10.1177/0883073810365737 (2010). (PMID: 10.1177/088307381036573720729507)
Bechi, G. et al. Rescuable folding defective NaV1.1 (SCN1A) mutants in epilepsy: properties, occurrence, and novel rescuing strategy with peptides targeted to the endoplasmic reticulum. Neurobiol. Dis. 75, 100–114, https://doi.org/10.1016/j.nbd.2014.12.028 (2015). (PMID: 10.1016/j.nbd.2014.12.02825576396)
Rusconi, R. et al. A rescuable folding defective Nav1. 1 (SCN1A) sodium channel mutant causes GEFS+: common mechanism in Nav1. 1 related epilepsies? Hum mutat 30, E747–E760, https://doi.org/10.1002/humu.21041 (2009). (PMID: 10.1002/humu.2104119402159)
Rusconi, R. et al. Modulatory proteins can rescue a trafficking defective epileptogenic Nav1. 1 Na+ channel mutant. J Neurosci 27, 11037–11046, https://doi.org/10.1523/JNEUROSCI.3515-07.2007 (2007). (PMID: 10.1523/JNEUROSCI.3515-07.2007179284456672853)
Thompson, C. H., Porter, J. C., Kahlig, K. M., Daniels, M. A. & George, A. L. Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression. J Biol Chem 287, 42001–42008, https://doi.org/10.1074/jbc.M112.421883 (2012). (PMID: 10.1074/jbc.M112.421883230869563516746)
Sugawara, T. et al. Nav1. 1 channels with mutations of severe myoclonic epilepsy in infancy display attenuated currents. Epilepsy Res. 54, 201–207, https://doi.org/10.1016/S0920-1211(03)00084-6 (2003). (PMID: 10.1016/S0920-1211(03)00084-612837571)
Bechi, G. et al. Pure haploinsufficiency for Dravet syndrome NaV1. 1 (SCN1A) sodium channel truncating mutations. Epilepsia 53, 87–100, https://doi.org/10.1111/j.1528-1167.2011.03346.x (2012). (PMID: 10.1111/j.1528-1167.2011.03346.x22150645)
Ohmori, I., Kahlig, K. M., Rhodes, T. H., Wang, D. W. & George, A. L. Jr Nonfunctional SCN1A is common in severe myoclonic epilepsy of infancy. Epilepsia 47, 1636–1642, https://doi.org/10.1111/j.1528-1167.2006.00643.x (2006). (PMID: 10.1111/j.1528-1167.2006.00643.x17054685)
Rhodes, T. H., Lossin, C., Vanoye, C. G., Wang, D. W. & George, A. L. Noninactivating voltage-gated sodium channels in severe myoclonic epilepsy of infancy. Proc. Natl. Acad. Sci. USA 101, 11147–11152, https://doi.org/10.1073/pnas.0402482101 (2004). (PMID: 10.1073/pnas.040248210115263074)
Lossin, C. et al. Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A. J. Neurosci. 23, 11289–11295, https://doi.org/10.1523/JNEUROSCI.23-36-11289.2003 (2003). (PMID: 10.1523/JNEUROSCI.23-36-11289.2003146729926740520)
Spampanato, J., Escayg, A., Meisler, M. & Goldin, A. Generalized epilepsy with febrile seizures plus type 2 mutation W1204R alters voltage-dependent gating of Nav1.1 sodium channels. Neuroscience 116, 37–48, https://doi.org/10.1016/S0306-4522(02)00698-X (2003). (PMID: 10.1016/S0306-4522(02)00698-X12535936)
Volkers, L. et al. Nav1.1 dysfunction in genetic epilepsy with febrile seizures‐plus or Dravet syndrome. Eur. J. Neurosci. 34, 1268–1275, https://doi.org/10.1111/j.1460-9568.2011.07826.x (2011). (PMID: 10.1111/j.1460-9568.2011.07826.x218643213195841)
Berecki, G. et al. SCN1A gain of function in early infantile encephalopathy. Ann. Neurol. 85, 514–525, https://doi.org/10.1002/ana.25438 (2019). (PMID: 10.1002/ana.2543830779207)
Rhodes, T. H. et al. Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic–clonic seizures. J. Physiol. 569, 433–445, https://doi.org/10.1113/jphysiol.2005.094326 (2005). (PMID: 10.1113/jphysiol.2005.094326162103581464244)
Djémié, T. et al. Pitfalls in genetic testing: the story of missed SCN1A mutations. Mol. Genet. Genomic Med. 4, 457–464, https://doi.org/10.1002/mgg3.217 (2016). (PMID: 10.1002/mgg3.217274655854947864)
Ebach, K. et al. SCN1A mutation analysis in myoclonic astatic epilepsy and severe idiopathic generalized epilepsy of infancy with generalized tonic-clonic seizures. Neuropediatrics 36, 210–213, https://doi.org/10.1055/s-2005-865607 (2005). (PMID: 10.1055/s-2005-86560715944908)
Long, Y. S. et al. Identification of the promoter region and the 5′‐untranslated exons of the human voltage‐gated sodium channel Nav1. 1 gene (SCN1A) and enhancement of gene expression by the 5′‐untranslated exons. J. Neurosci. Res. 86, 3375–3381, https://doi.org/10.1002/jnr.21790 (2008). (PMID: 10.1002/jnr.2179018655196)
Martin, M. S. et al. The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum. Mol. Genet. 16, 2892–2899, https://doi.org/10.1093/hmg/ddm248 (2007). (PMID: 10.1093/hmg/ddm24817881658)
Ohmori, I. et al. CACNA1A variants may modify the epileptic phenotype of Dravet syndrome. Neurobiol. Dis. 50, 209–217, https://doi.org/10.1016/j.nbd.2012.10.016 (2013). (PMID: 10.1016/j.nbd.2012.10.01623103419)
Singh, N. A. et al. A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS genet. 5, e1000649, https://doi.org/10.1371/journal.pgen.1000649 (2009). (PMID: 10.1371/journal.pgen.1000649197631612730533)
Zeng, T. et al. A novel variant in the 3′ UTR of human SCN1A gene from a patient with Dravet syndrome decreases mRNA stability mediated by GAPDH’s binding. Hum. Genet. 133, 801–811, https://doi.org/10.1007/s00439-014-1422-8 (2014). (PMID: 10.1007/s00439-014-1422-824464349)
Cestèle, S., Schiavon, E., Rusconi, R., Franceschetti, S. & Mantegazza, M. Nonfunctional NaV1. 1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects. Proc Natl Acad Sci USA 110, 17546–17551, https://doi.org/10.1073/pnas.1309827110 (2013). (PMID: 10.1073/pnas.130982711024101488)
Dhifallah, S. et al. Gain of function for the SCN1A/hNav1. 1-L1670W mutation responsible for familial hemiplegic migraine. Front Mol Neurosci 11, 232, https://doi.org/10.3389/fnmol.2018.00232 (2018). (PMID: 10.3389/fnmol.2018.00232300385596046441)
Fan, C. et al. Early-onset familial hemiplegic migraine due to a novel SCN1A mutation. Cephalalgia 36, 1238–1247, https://doi.org/10.1177/0333102415608360 (2016). (PMID: 10.1177/0333102415608360267630455105328)
Bertelli, S., Barbieri, R., Pusch, M. & Gavazzo, P. Gain of function of sporadic/familial hemiplegic migraine-causing SCN1A mutations: use of an optimized cDNA. Cephalalgia 39, 477–488, https://doi.org/10.1177/0333102418788336 (2019). (PMID: 10.1177/033310241878833629986598)
Guerrini, R. et al. Variable epilepsy phenotypes associated with a familial intragenic deletion of the SCN1A gene. Epilepsia 51, 2474–2477, https://doi.org/10.1111/j.1528-1167.2010.02790.x (2010). (PMID: 10.1111/j.1528-1167.2010.02790.x21204810)
Salgueiro-Pereira, A. R. et al. A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies. Neurobiol dis 125, 31–44, https://doi.org/10.1016/j.nbd.2019.01.006 (2019). (PMID: 10.1016/j.nbd.2019.01.00630659983)
Jiao, J. et al. Modeling Dravet syndrome using induced pluripotent stem cells (iPSCs) and directly converted neurons. Hum. Mol. Genet. 22, 4241–4252, https://doi.org/10.1093/hmg/ddt275 (2013). (PMID: 10.1093/hmg/ddt27523773995)
Kim, H. W. et al. Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients. Brain Dev. 40, 287–298, https://doi.org/10.1016/j.braindev.2017.12.002 (2018). (PMID: 10.1016/j.braindev.2017.12.00229295803)
Liu, Y. et al. Dravet syndrome patient‐derived neurons suggest a novel epilepsy mechanism. Ann. Neurol. 74, 128–139, https://doi.org/10.1002/ana.23897 (2013). (PMID: 10.1002/ana.23897238215403775921)
Sun, Y. et al. A deleterious Nav1. 1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. Elife 5, e13073, https://doi.org/10.7554/eLife.13073 (2016). (PMID: 10.7554/eLife.13073274587974961470)
Lossin, C. A catalog of SCN1A variants. Brain Dev. 31, 114–130, https://doi.org/10.1016/j.braindev.2008.07.011 (2009). (PMID: 10.1016/j.braindev.2008.07.01118804930)
Schaller, K., Krzemien, D., McKenna, N. & Caldwell, J. Alternatively spliced sodium channel transcripts in brain and muscle. J. Neurosci. 12, 1370–1381, https://doi.org/10.1523/JNEUROSCI.12-04-01370.1992 (1992). (PMID: 10.1523/JNEUROSCI.12-04-01370.199213134936575792)
Mantegazza, M. et al. Identification of an Nav1. 1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. Proc. Natl. Acad. Sci. USA 102, 18177–18182, https://doi.org/10.1073/pnas.0506818102 (2005). (PMID: 10.1073/pnas.050681810216326807)
Capriotti, E., Altman, R. B. & Bromberg, Y. Collective judgment predicts disease-associated single nucleotide variants. BMC Genomics 14, S2, https://doi.org/10.1186/1471-2164-14-S3-S2 (2013). (PMID: 10.1186/1471-2164-14-S3-S2238198463839641)
Bendl, J. et al. PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput. Biol. 10, e1003440, https://doi.org/10.1371/journal.pcbi.1003440 (2014). (PMID: 10.1371/journal.pcbi.1003440244539613894168)
Simossis, V. A. & Heringa, J. PRALINE: a multiple sequence alignment toolbox that integrates homology-extended and secondary structure information. Nucleic Acids Res. 33, W289–W294, https://doi.org/10.1093/nar/gki390 (2005). (PMID: 10.1093/nar/gki390159804721160151)
Substance Nomenclature:: 0 (NAV1.1 Voltage-Gated Sodium Channel)
0 (Recombinant Proteins)
0 (SCN1A protein, human)
9NEZ333N27 (Sodium)
Entry Date(s):: Date Created: 20200626 Date Completed: 20201221 Latest Revision: 20210624
Update Code:: 20240105
PubMed Central ID:: PMC7314844
DOI:: 10.1038/s41598-020-67215-y
PMID:: 32581296
: Czasopismo naukowe

Pełny tekst

Mutations in the voltage-gated sodium channel Na v 1.1 (SCN1A) are linked to various epileptic phenotypes with different severities, however, the consequences of newly identified SCN1A variants on patient phenotype is uncertain so far. The functional impact of nine SCN1A variants, including five novel variants identified in this study, was studied using whole-cell patch-clamp recordings measurement of mutant Na v 1.1 channels expressed in HEK293T mammalian cells. E78X, W384X, E1587K, and R1596C channels failed to produce measurable sodium currents, indicating complete loss of channel function. E788K and M909K variants resulted in partial loss of function by exhibiting reduced current density, depolarizing shifts of the activation and hyperpolarizing shifts of the inactivation curves, and slower recovery from inactivation. Hyperpolarizing shifts of the activation and inactivation curves were observed in D249E channels along with slower recovery from inactivation. Slower recovery from inactivation was observed in E78D and T1934I with reduced current density in T1934I channels. Various functional effects were observed with the lack of sodium current being mainly associated with severe phenotypes and milder symptoms with less damaging channel alteration. In vitro functional analysis is thus fundamental for elucidation of the molecular mechanisms of epilepsy, to guide patients' treatment, and finally indicate misdiagnosis of SCN1A related epilepsies.

Zaloguj się, aby uzyskać dostęp do pełnego tekstu.

Informacja