Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this...
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Autor*in:	Grzegorz Witkowski [verfasserIn] Bartlomiej Szulczyk [verfasserIn] Ewa Nurowska [verfasserIn] Marta Jurek [verfasserIn] Michal Pasierski [verfasserIn] Agata Lipiec [verfasserIn] Agnieszka Charzewska [verfasserIn] Mateusz Dawidziuk [verfasserIn] Michal Milewski [verfasserIn] Szymon Owsiak [verfasserIn] Rafal Rola [verfasserIn] Halina Sienkiewicz Jarosz [verfasserIn] Dorota Hoffman-Zacharska [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	voltage gated sodium channels epilepsy patch clamp nerve excitability study

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 25(2024), 3, p 1745
Übergeordnetes Werk:	volume:25 ; year:2024 ; number:3, p 1745

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms25031745

Katalog-ID:	DOAJ094492018

Internformat


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allfields	10.3390/ijms25031745 doi (DE-627)DOAJ094492018 (DE-599)DOAJ606e0ed43174450484e2849840b560cd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Grzegorz Witkowski verfasserin aut Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study Biology (General) Chemistry Bartlomiej Szulczyk verfasserin aut Ewa Nurowska verfasserin aut Marta Jurek verfasserin aut Michal Pasierski verfasserin aut Agata Lipiec verfasserin aut Agnieszka Charzewska verfasserin aut Mateusz Dawidziuk verfasserin aut Michal Milewski verfasserin aut Szymon Owsiak verfasserin aut Rafal Rola verfasserin aut Halina Sienkiewicz Jarosz verfasserin aut Dorota Hoffman-Zacharska verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 3, p 1745 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:3, p 1745 https://doi.org/10.3390/ijms25031745 kostenfrei https://doaj.org/article/606e0ed43174450484e2849840b560cd kostenfrei https://www.mdpi.com/1422-0067/25/3/1745 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 3, p 1745
spelling	10.3390/ijms25031745 doi (DE-627)DOAJ094492018 (DE-599)DOAJ606e0ed43174450484e2849840b560cd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Grzegorz Witkowski verfasserin aut Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study Biology (General) Chemistry Bartlomiej Szulczyk verfasserin aut Ewa Nurowska verfasserin aut Marta Jurek verfasserin aut Michal Pasierski verfasserin aut Agata Lipiec verfasserin aut Agnieszka Charzewska verfasserin aut Mateusz Dawidziuk verfasserin aut Michal Milewski verfasserin aut Szymon Owsiak verfasserin aut Rafal Rola verfasserin aut Halina Sienkiewicz Jarosz verfasserin aut Dorota Hoffman-Zacharska verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 3, p 1745 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:3, p 1745 https://doi.org/10.3390/ijms25031745 kostenfrei https://doaj.org/article/606e0ed43174450484e2849840b560cd kostenfrei https://www.mdpi.com/1422-0067/25/3/1745 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 3, p 1745
allfields_unstemmed	10.3390/ijms25031745 doi (DE-627)DOAJ094492018 (DE-599)DOAJ606e0ed43174450484e2849840b560cd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Grzegorz Witkowski verfasserin aut Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study Biology (General) Chemistry Bartlomiej Szulczyk verfasserin aut Ewa Nurowska verfasserin aut Marta Jurek verfasserin aut Michal Pasierski verfasserin aut Agata Lipiec verfasserin aut Agnieszka Charzewska verfasserin aut Mateusz Dawidziuk verfasserin aut Michal Milewski verfasserin aut Szymon Owsiak verfasserin aut Rafal Rola verfasserin aut Halina Sienkiewicz Jarosz verfasserin aut Dorota Hoffman-Zacharska verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 3, p 1745 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:3, p 1745 https://doi.org/10.3390/ijms25031745 kostenfrei https://doaj.org/article/606e0ed43174450484e2849840b560cd kostenfrei https://www.mdpi.com/1422-0067/25/3/1745 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 3, p 1745
allfieldsGer	10.3390/ijms25031745 doi (DE-627)DOAJ094492018 (DE-599)DOAJ606e0ed43174450484e2849840b560cd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Grzegorz Witkowski verfasserin aut Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study Biology (General) Chemistry Bartlomiej Szulczyk verfasserin aut Ewa Nurowska verfasserin aut Marta Jurek verfasserin aut Michal Pasierski verfasserin aut Agata Lipiec verfasserin aut Agnieszka Charzewska verfasserin aut Mateusz Dawidziuk verfasserin aut Michal Milewski verfasserin aut Szymon Owsiak verfasserin aut Rafal Rola verfasserin aut Halina Sienkiewicz Jarosz verfasserin aut Dorota Hoffman-Zacharska verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 3, p 1745 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:3, p 1745 https://doi.org/10.3390/ijms25031745 kostenfrei https://doaj.org/article/606e0ed43174450484e2849840b560cd kostenfrei https://www.mdpi.com/1422-0067/25/3/1745 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 3, p 1745
allfieldsSound	10.3390/ijms25031745 doi (DE-627)DOAJ094492018 (DE-599)DOAJ606e0ed43174450484e2849840b560cd DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Grzegorz Witkowski verfasserin aut Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study Biology (General) Chemistry Bartlomiej Szulczyk verfasserin aut Ewa Nurowska verfasserin aut Marta Jurek verfasserin aut Michal Pasierski verfasserin aut Agata Lipiec verfasserin aut Agnieszka Charzewska verfasserin aut Mateusz Dawidziuk verfasserin aut Michal Milewski verfasserin aut Szymon Owsiak verfasserin aut Rafal Rola verfasserin aut Halina Sienkiewicz Jarosz verfasserin aut Dorota Hoffman-Zacharska verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 3, p 1745 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:3, p 1745 https://doi.org/10.3390/ijms25031745 kostenfrei https://doaj.org/article/606e0ed43174450484e2849840b560cd kostenfrei https://www.mdpi.com/1422-0067/25/3/1745 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 3, p 1745
language	English
source	In International Journal of Molecular Sciences 25(2024), 3, p 1745 volume:25 year:2024 number:3, p 1745
sourceStr	In International Journal of Molecular Sciences 25(2024), 3, p 1745 volume:25 year:2024 number:3, p 1745
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Grzegorz Witkowski @@aut@@ Bartlomiej Szulczyk @@aut@@ Ewa Nurowska @@aut@@ Marta Jurek @@aut@@ Michal Pasierski @@aut@@ Agata Lipiec @@aut@@ Agnieszka Charzewska @@aut@@ Mateusz Dawidziuk @@aut@@ Michal Milewski @@aut@@ Szymon Owsiak @@aut@@ Rafal Rola @@aut@@ Halina Sienkiewicz Jarosz @@aut@@ Dorota Hoffman-Zacharska @@aut@@
publishDateDaySort_date	2024-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ094492018
language_de	englisch
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callnumber-first	Q - Science
author	Grzegorz Witkowski
spellingShingle	Grzegorz Witkowski misc QH301-705.5 misc QD1-999 misc voltage gated sodium channels misc <i<SCN1A</i< mutation misc epilepsy misc patch clamp misc nerve excitability study misc Biology (General) misc Chemistry Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes
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topic_title	QH301-705.5 QD1-999 Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes voltage gated sodium channels <i<SCN1A</i< mutation epilepsy patch clamp nerve excitability study
topic	misc QH301-705.5 misc QD1-999 misc voltage gated sodium channels misc <i<SCN1A</i< mutation misc epilepsy misc patch clamp misc nerve excitability study misc Biology (General) misc Chemistry
topic_unstemmed	misc QH301-705.5 misc QD1-999 misc voltage gated sodium channels misc <i<SCN1A</i< mutation misc epilepsy misc patch clamp misc nerve excitability study misc Biology (General) misc Chemistry
topic_browse	misc QH301-705.5 misc QD1-999 misc voltage gated sodium channels misc <i<SCN1A</i< mutation misc epilepsy misc patch clamp misc nerve excitability study misc Biology (General) misc Chemistry
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title	Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes
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title_full	Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes
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title_sort	functional characteristics of the nav1.1 p.arg1596cys mutation associated with varying severity of epilepsy phenotypes
callnumber	QH301-705.5
title_auth	Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes
abstract	Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.
abstractGer	Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.
abstract_unstemmed	Mutations of the <i<SCN1A</i< gene, which encodes the voltage-dependent Na<sup<+</sup< channel’s α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes’ variability in the family of five <i<SCN1A</i< gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing <i<SCN1A</i<-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype.
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title_short	Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes
url	https://doi.org/10.3390/ijms25031745 https://doaj.org/article/606e0ed43174450484e2849840b560cd https://www.mdpi.com/1422-0067/25/3/1745 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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Functional Characteristics of the Nav1.1 p.Arg1596Cys Mutation Associated with Varying Severity of Epilepsy Phenotypes

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