A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability

HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep stru...
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Autor*in:	Giulia Campostrini [verfasserIn] Jacopo C. DiFrancesco [verfasserIn] Barbara Castellotti [verfasserIn] Raffaella Milanesi [verfasserIn] Tomaso Gnecchi-Ruscone [verfasserIn] Mattia Bonzanni [verfasserIn] Annalisa Bucchi [verfasserIn] Mirko Baruscotti [verfasserIn] Carlo Ferrarese [verfasserIn] Silvana Franceschetti [verfasserIn] Laura Canafoglia [verfasserIn] Francesca Ragona [verfasserIn] Elena Freri [verfasserIn] Angelo Labate [verfasserIn] Antonio Gambardella [verfasserIn] Cinzia Costa [verfasserIn] Cinzia Gellera [verfasserIn] Tiziana Granata [verfasserIn] Andrea Barbuti [verfasserIn] Dario DiFrancesco [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability

Übergeordnetes Werk:	In: Frontiers in Molecular Neuroscience - Frontiers Media S.A., 2008, 11(2018)
Übergeordnetes Werk:	volume:11 ; year:2018

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fnmol.2018.00269

Katalog-ID:	DOAJ003990516

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allfields	10.3389/fnmol.2018.00269 doi (DE-627)DOAJ003990516 (DE-599)DOAJ92864aee37004121b3bebabcbb21ec80 DE-627 ger DE-627 rakwb eng RC321-571 Giulia Campostrini verfasserin aut A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies. HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Jacopo C. DiFrancesco verfasserin aut Barbara Castellotti verfasserin aut Raffaella Milanesi verfasserin aut Tomaso Gnecchi-Ruscone verfasserin aut Mattia Bonzanni verfasserin aut Annalisa Bucchi verfasserin aut Mirko Baruscotti verfasserin aut Carlo Ferrarese verfasserin aut Silvana Franceschetti verfasserin aut Laura Canafoglia verfasserin aut Francesca Ragona verfasserin aut Elena Freri verfasserin aut Angelo Labate verfasserin aut Antonio Gambardella verfasserin aut Cinzia Costa verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Frontiers in Molecular Neuroscience Frontiers Media S.A., 2008 11(2018) (DE-627)579826449 (DE-600)2452967-9 16625099 nnns volume:11 year:2018 https://doi.org/10.3389/fnmol.2018.00269 kostenfrei https://doaj.org/article/92864aee37004121b3bebabcbb21ec80 kostenfrei https://www.frontiersin.org/article/10.3389/fnmol.2018.00269/full kostenfrei https://doaj.org/toc/1662-5099 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 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 11 2018
spelling	10.3389/fnmol.2018.00269 doi (DE-627)DOAJ003990516 (DE-599)DOAJ92864aee37004121b3bebabcbb21ec80 DE-627 ger DE-627 rakwb eng RC321-571 Giulia Campostrini verfasserin aut A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies. HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Jacopo C. DiFrancesco verfasserin aut Barbara Castellotti verfasserin aut Raffaella Milanesi verfasserin aut Tomaso Gnecchi-Ruscone verfasserin aut Mattia Bonzanni verfasserin aut Annalisa Bucchi verfasserin aut Mirko Baruscotti verfasserin aut Carlo Ferrarese verfasserin aut Silvana Franceschetti verfasserin aut Laura Canafoglia verfasserin aut Francesca Ragona verfasserin aut Elena Freri verfasserin aut Angelo Labate verfasserin aut Antonio Gambardella verfasserin aut Cinzia Costa verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Frontiers in Molecular Neuroscience Frontiers Media S.A., 2008 11(2018) (DE-627)579826449 (DE-600)2452967-9 16625099 nnns volume:11 year:2018 https://doi.org/10.3389/fnmol.2018.00269 kostenfrei https://doaj.org/article/92864aee37004121b3bebabcbb21ec80 kostenfrei https://www.frontiersin.org/article/10.3389/fnmol.2018.00269/full kostenfrei https://doaj.org/toc/1662-5099 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 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 11 2018
allfields_unstemmed	10.3389/fnmol.2018.00269 doi (DE-627)DOAJ003990516 (DE-599)DOAJ92864aee37004121b3bebabcbb21ec80 DE-627 ger DE-627 rakwb eng RC321-571 Giulia Campostrini verfasserin aut A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies. HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Jacopo C. DiFrancesco verfasserin aut Barbara Castellotti verfasserin aut Raffaella Milanesi verfasserin aut Tomaso Gnecchi-Ruscone verfasserin aut Mattia Bonzanni verfasserin aut Annalisa Bucchi verfasserin aut Mirko Baruscotti verfasserin aut Carlo Ferrarese verfasserin aut Silvana Franceschetti verfasserin aut Laura Canafoglia verfasserin aut Francesca Ragona verfasserin aut Elena Freri verfasserin aut Angelo Labate verfasserin aut Antonio Gambardella verfasserin aut Cinzia Costa verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Frontiers in Molecular Neuroscience Frontiers Media S.A., 2008 11(2018) (DE-627)579826449 (DE-600)2452967-9 16625099 nnns volume:11 year:2018 https://doi.org/10.3389/fnmol.2018.00269 kostenfrei https://doaj.org/article/92864aee37004121b3bebabcbb21ec80 kostenfrei https://www.frontiersin.org/article/10.3389/fnmol.2018.00269/full kostenfrei https://doaj.org/toc/1662-5099 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 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 11 2018
allfieldsGer	10.3389/fnmol.2018.00269 doi (DE-627)DOAJ003990516 (DE-599)DOAJ92864aee37004121b3bebabcbb21ec80 DE-627 ger DE-627 rakwb eng RC321-571 Giulia Campostrini verfasserin aut A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies. HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Jacopo C. DiFrancesco verfasserin aut Barbara Castellotti verfasserin aut Raffaella Milanesi verfasserin aut Tomaso Gnecchi-Ruscone verfasserin aut Mattia Bonzanni verfasserin aut Annalisa Bucchi verfasserin aut Mirko Baruscotti verfasserin aut Carlo Ferrarese verfasserin aut Silvana Franceschetti verfasserin aut Laura Canafoglia verfasserin aut Francesca Ragona verfasserin aut Elena Freri verfasserin aut Angelo Labate verfasserin aut Antonio Gambardella verfasserin aut Cinzia Costa verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Frontiers in Molecular Neuroscience Frontiers Media S.A., 2008 11(2018) (DE-627)579826449 (DE-600)2452967-9 16625099 nnns volume:11 year:2018 https://doi.org/10.3389/fnmol.2018.00269 kostenfrei https://doaj.org/article/92864aee37004121b3bebabcbb21ec80 kostenfrei https://www.frontiersin.org/article/10.3389/fnmol.2018.00269/full kostenfrei https://doaj.org/toc/1662-5099 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 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 11 2018
allfieldsSound	10.3389/fnmol.2018.00269 doi (DE-627)DOAJ003990516 (DE-599)DOAJ92864aee37004121b3bebabcbb21ec80 DE-627 ger DE-627 rakwb eng RC321-571 Giulia Campostrini verfasserin aut A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies. HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Jacopo C. DiFrancesco verfasserin aut Barbara Castellotti verfasserin aut Raffaella Milanesi verfasserin aut Tomaso Gnecchi-Ruscone verfasserin aut Mattia Bonzanni verfasserin aut Annalisa Bucchi verfasserin aut Mirko Baruscotti verfasserin aut Carlo Ferrarese verfasserin aut Silvana Franceschetti verfasserin aut Laura Canafoglia verfasserin aut Francesca Ragona verfasserin aut Elena Freri verfasserin aut Angelo Labate verfasserin aut Antonio Gambardella verfasserin aut Cinzia Costa verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Frontiers in Molecular Neuroscience Frontiers Media S.A., 2008 11(2018) (DE-627)579826449 (DE-600)2452967-9 16625099 nnns volume:11 year:2018 https://doi.org/10.3389/fnmol.2018.00269 kostenfrei https://doaj.org/article/92864aee37004121b3bebabcbb21ec80 kostenfrei https://www.frontiersin.org/article/10.3389/fnmol.2018.00269/full kostenfrei https://doaj.org/toc/1662-5099 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 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 11 2018
language	English
source	In Frontiers in Molecular Neuroscience 11(2018) volume:11 year:2018
sourceStr	In Frontiers in Molecular Neuroscience 11(2018) volume:11 year:2018
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability Neurosciences. Biological psychiatry. Neuropsychiatry
isfreeaccess_bool	true
container_title	Frontiers in Molecular Neuroscience
authorswithroles_txt_mv	Giulia Campostrini @@aut@@ Jacopo C. DiFrancesco @@aut@@ Barbara Castellotti @@aut@@ Raffaella Milanesi @@aut@@ Tomaso Gnecchi-Ruscone @@aut@@ Mattia Bonzanni @@aut@@ Annalisa Bucchi @@aut@@ Mirko Baruscotti @@aut@@ Carlo Ferrarese @@aut@@ Silvana Franceschetti @@aut@@ Laura Canafoglia @@aut@@ Francesca Ragona @@aut@@ Elena Freri @@aut@@ Angelo Labate @@aut@@ Antonio Gambardella @@aut@@ Cinzia Costa @@aut@@ Cinzia Gellera @@aut@@ Tiziana Granata @@aut@@ Andrea Barbuti @@aut@@ Dario DiFrancesco @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	579826449
id	DOAJ003990516
language_de	englisch
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callnumber-first	R - Medicine
author	Giulia Campostrini
spellingShingle	Giulia Campostrini misc RC321-571 misc HCN4 misc epilepsy misc ion channels misc myoclonic epilepsy of infancy misc neuronal excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability
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topic_title	RC321-571 A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability HCN4 epilepsy ion channels myoclonic epilepsy of infancy neuronal excitability
topic	misc RC321-571 misc HCN4 misc epilepsy misc ion channels misc myoclonic epilepsy of infancy misc neuronal excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_unstemmed	misc RC321-571 misc HCN4 misc epilepsy misc ion channels misc myoclonic epilepsy of infancy misc neuronal excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_browse	misc RC321-571 misc HCN4 misc epilepsy misc ion channels misc myoclonic epilepsy of infancy misc neuronal excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry
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title	A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability
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title_full	A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability
author_sort	Giulia Campostrini
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author_browse	Giulia Campostrini Jacopo C. DiFrancesco Barbara Castellotti Raffaella Milanesi Tomaso Gnecchi-Ruscone Mattia Bonzanni Annalisa Bucchi Mirko Baruscotti Carlo Ferrarese Silvana Franceschetti Laura Canafoglia Francesca Ragona Elena Freri Angelo Labate Antonio Gambardella Cinzia Costa Cinzia Gellera Tiziana Granata Andrea Barbuti Dario DiFrancesco
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doi_str_mv	10.3389/fnmol.2018.00269
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title_sort	loss-of-function hcn4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability
callnumber	RC321-571
title_auth	A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability
abstract	HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies.
abstractGer	HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies.
abstract_unstemmed	HCN channels are highly expressed and functionally relevant in neurons and increasing evidence demonstrates their involvement in the etiology of human epilepsies. Among HCN isoforms, HCN4 is important in cardiac tissue, where it underlies pacemaker activity. Despite being expressed also in deep structures of the brain, mutations of this channel functionally shown to be associated with epilepsy have not been reported yet. Using Next Generation Sequencing for the screening of patients with idiopathic epilepsy, we identified the p.Arg550Cys (c.1648C>T) heterozygous mutation on HCN4 in two brothers affected by benign myoclonic epilepsy of infancy. Functional characterization in heterologous expression system and in neurons showed that the mutation determines a loss of function of HCN4 contribution to activity and an increase of neuronal discharge, potentially predisposing to epilepsy. Expressed in cardiomyocytes, mutant channels activate at slightly more negative voltages than wild-type (WT), in accordance with borderline bradycardia. While HCN4 variants have been frequently associated with cardiac arrhythmias, these data represent the first experimental evidence that functional alteration of HCN4 can also be involved in human epilepsy through a loss-of-function effect and associated increased neuronal excitability. Since HCN4 appears to be highly expressed in deep brain structures only early during development, our data provide a potential explanation for a link between dysfunctional HCN4 and infantile epilepsy. These findings suggest that it may be useful to include HCN4 screening to extend the knowledge of the genetic causes of infantile epilepsies, potentially paving the way for the identification of innovative therapeutic strategies.
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title_short	A Loss-of-Function HCN4 Mutation Associated With Familial Benign Myoclonic Epilepsy in Infancy Causes Increased Neuronal Excitability
url	https://doi.org/10.3389/fnmol.2018.00269 https://doaj.org/article/92864aee37004121b3bebabcbb21ec80 https://www.frontiersin.org/article/10.3389/fnmol.2018.00269/full https://doaj.org/toc/1662-5099
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author2	Jacopo C. DiFrancesco Barbara Castellotti Raffaella Milanesi Tomaso Gnecchi-Ruscone Mattia Bonzanni Annalisa Bucchi Mirko Baruscotti Carlo Ferrarese Silvana Franceschetti Laura Canafoglia Francesca Ragona Elena Freri Angelo Labate Antonio Gambardella Cinzia Costa Cinzia Gellera Tiziana Granata Andrea Barbuti Dario DiFrancesco
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up_date	2024-07-03T21:19:22.576Z
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