A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability

The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hip...
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Autor*in:	Mattia Bonzanni [verfasserIn] Jacopo C. DiFrancesco [verfasserIn] Raffaella Milanesi [verfasserIn] Giulia Campostrini [verfasserIn] Barbara Castellotti [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] Ilaria Rivolta [verfasserIn] Cinzia Gellera [verfasserIn] Tiziana Granata [verfasserIn] Andrea Barbuti [verfasserIn] Dario DiFrancesco [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability

Übergeordnetes Werk:	In: Neurobiology of Disease - Elsevier, 2021, 118(2018), Seite 55-63
Übergeordnetes Werk:	volume:118 ; year:2018 ; pages:55-63

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.nbd.2018.06.012

Katalog-ID:	DOAJ059525312

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245	1	2	\|a A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
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520			\|a The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
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650		4	\|a Genetic generalized epilepsy
650		4	\|a Electrophysiology
650		4	\|a Membrane excitability
653		0	\|a Neurosciences. Biological psychiatry. Neuropsychiatry
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700	0		\|a Andrea Barbuti \|e verfasserin \|4 aut
700	0		\|a Dario DiFrancesco \|e verfasserin \|4 aut
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allfields	10.1016/j.nbd.2018.06.012 doi (DE-627)DOAJ059525312 (DE-599)DOAJd23258a9e43a4f519934f140b2c934bc DE-627 ger DE-627 rakwb eng RC321-571 Mattia Bonzanni verfasserin aut A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies. HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Raffaella Milanesi verfasserin aut Giulia Campostrini verfasserin aut Barbara Castellotti 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 Ilaria Rivolta verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Neurobiology of Disease Elsevier, 2021 118(2018), Seite 55-63 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:118 year:2018 pages:55-63 https://doi.org/10.1016/j.nbd.2018.06.012 kostenfrei https://doaj.org/article/d23258a9e43a4f519934f140b2c934bc kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996118301918 kostenfrei https://doaj.org/toc/1095-953X 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_32 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_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 118 2018 55-63
spelling	10.1016/j.nbd.2018.06.012 doi (DE-627)DOAJ059525312 (DE-599)DOAJd23258a9e43a4f519934f140b2c934bc DE-627 ger DE-627 rakwb eng RC321-571 Mattia Bonzanni verfasserin aut A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies. HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Raffaella Milanesi verfasserin aut Giulia Campostrini verfasserin aut Barbara Castellotti 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 Ilaria Rivolta verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Neurobiology of Disease Elsevier, 2021 118(2018), Seite 55-63 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:118 year:2018 pages:55-63 https://doi.org/10.1016/j.nbd.2018.06.012 kostenfrei https://doaj.org/article/d23258a9e43a4f519934f140b2c934bc kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996118301918 kostenfrei https://doaj.org/toc/1095-953X 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_32 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_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 118 2018 55-63
allfields_unstemmed	10.1016/j.nbd.2018.06.012 doi (DE-627)DOAJ059525312 (DE-599)DOAJd23258a9e43a4f519934f140b2c934bc DE-627 ger DE-627 rakwb eng RC321-571 Mattia Bonzanni verfasserin aut A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies. HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Raffaella Milanesi verfasserin aut Giulia Campostrini verfasserin aut Barbara Castellotti 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 Ilaria Rivolta verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Neurobiology of Disease Elsevier, 2021 118(2018), Seite 55-63 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:118 year:2018 pages:55-63 https://doi.org/10.1016/j.nbd.2018.06.012 kostenfrei https://doaj.org/article/d23258a9e43a4f519934f140b2c934bc kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996118301918 kostenfrei https://doaj.org/toc/1095-953X 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_32 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_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 118 2018 55-63
allfieldsGer	10.1016/j.nbd.2018.06.012 doi (DE-627)DOAJ059525312 (DE-599)DOAJd23258a9e43a4f519934f140b2c934bc DE-627 ger DE-627 rakwb eng RC321-571 Mattia Bonzanni verfasserin aut A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies. HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Raffaella Milanesi verfasserin aut Giulia Campostrini verfasserin aut Barbara Castellotti 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 Ilaria Rivolta verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Neurobiology of Disease Elsevier, 2021 118(2018), Seite 55-63 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:118 year:2018 pages:55-63 https://doi.org/10.1016/j.nbd.2018.06.012 kostenfrei https://doaj.org/article/d23258a9e43a4f519934f140b2c934bc kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996118301918 kostenfrei https://doaj.org/toc/1095-953X 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_32 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_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 118 2018 55-63
allfieldsSound	10.1016/j.nbd.2018.06.012 doi (DE-627)DOAJ059525312 (DE-599)DOAJd23258a9e43a4f519934f140b2c934bc DE-627 ger DE-627 rakwb eng RC321-571 Mattia Bonzanni verfasserin aut A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies. HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability Neurosciences. Biological psychiatry. Neuropsychiatry Jacopo C. DiFrancesco verfasserin aut Raffaella Milanesi verfasserin aut Giulia Campostrini verfasserin aut Barbara Castellotti 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 Ilaria Rivolta verfasserin aut Cinzia Gellera verfasserin aut Tiziana Granata verfasserin aut Andrea Barbuti verfasserin aut Dario DiFrancesco verfasserin aut In Neurobiology of Disease Elsevier, 2021 118(2018), Seite 55-63 (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:118 year:2018 pages:55-63 https://doi.org/10.1016/j.nbd.2018.06.012 kostenfrei https://doaj.org/article/d23258a9e43a4f519934f140b2c934bc kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996118301918 kostenfrei https://doaj.org/toc/1095-953X 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_32 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_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_165 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2010 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4700 AR 118 2018 55-63
language	English
source	In Neurobiology of Disease 118(2018), Seite 55-63 volume:118 year:2018 pages:55-63
sourceStr	In Neurobiology of Disease 118(2018), Seite 55-63 volume:118 year:2018 pages:55-63
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability Neurosciences. Biological psychiatry. Neuropsychiatry
isfreeaccess_bool	true
container_title	Neurobiology of Disease
authorswithroles_txt_mv	Mattia Bonzanni @@aut@@ Jacopo C. DiFrancesco @@aut@@ Raffaella Milanesi @@aut@@ Giulia Campostrini @@aut@@ Barbara Castellotti @@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@@ Ilaria Rivolta @@aut@@ Cinzia Gellera @@aut@@ Tiziana Granata @@aut@@ Andrea Barbuti @@aut@@ Dario DiFrancesco @@aut@@
publishDateDaySort_date	2018-01-01T00:00:00Z
hierarchy_top_id	268125414
id	DOAJ059525312
language_de	englisch
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callnumber-first	R - Medicine
author	Mattia Bonzanni
spellingShingle	Mattia Bonzanni misc RC321-571 misc HCN1 misc Genetic generalized epilepsy misc Electrophysiology misc Membrane excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
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topic_title	RC321-571 A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability HCN1 Genetic generalized epilepsy Electrophysiology Membrane excitability
topic	misc RC321-571 misc HCN1 misc Genetic generalized epilepsy misc Electrophysiology misc Membrane excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_unstemmed	misc RC321-571 misc HCN1 misc Genetic generalized epilepsy misc Electrophysiology misc Membrane excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_browse	misc RC321-571 misc HCN1 misc Genetic generalized epilepsy misc Electrophysiology misc Membrane excitability misc Neurosciences. Biological psychiatry. Neuropsychiatry
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title	A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
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title_full	A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
author_sort	Mattia Bonzanni
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author_browse	Mattia Bonzanni Jacopo C. DiFrancesco Raffaella Milanesi Giulia Campostrini Barbara Castellotti Annalisa Bucchi Mirko Baruscotti Carlo Ferrarese Silvana Franceschetti Laura Canafoglia Francesca Ragona Elena Freri Angelo Labate Antonio Gambardella Cinzia Costa Ilaria Rivolta Cinzia Gellera Tiziana Granata Andrea Barbuti Dario DiFrancesco
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title_sort	novel de novo hcn1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
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title_auth	A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
abstract	The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
abstractGer	The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
abstract_unstemmed	The causes of genetic epilepsies are unknown in the majority of patients. HCN ion channels have a widespread expression in neurons and increasing evidence demonstrates their functional involvement in human epilepsies. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus and de novo HCN1 point mutations have been recently associated with early infantile epileptic encephalopathy. So far, HCN1 mutations have not been reported in patients with idiopathic epilepsy. Using a Next Generation Sequencing approach, we identified the de novo heterozygous p.Leu157Val (c.469C < G) novel mutation in HCN1 in an adult male patient affected by genetic generalized epilepsy (GGE), with normal cognitive development. Electrophysiological analysis in heterologous expression model (CHO cells) and in neurons revealed that L157V is a loss-of-function, dominant negative mutation causing reduced HCN1 contribution to net inward current and responsible for an increased neuronal firing rate and excitability, potentially predisposing to epilepsy. These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.
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title_short	A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability
url	https://doi.org/10.1016/j.nbd.2018.06.012 https://doaj.org/article/d23258a9e43a4f519934f140b2c934bc http://www.sciencedirect.com/science/article/pii/S0969996118301918 https://doaj.org/toc/1095-953X
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up_date	2024-07-03T23:51:31.324Z
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These data represent the first evidence that autosomal dominant missense mutations of HCN1 can also be involved in GGE, without the characteristics of epileptic encephalopathy reported previously. It will be important to include HCN1 screening in patients with GGE, in order to extend the knowledge of the genetic causes of idiopathic epilepsies, thus paving the way for the identification of innovative therapeutic strategies.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">HCN1</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Genetic generalized epilepsy</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Electrophysiology</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Membrane excitability</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neurosciences. Biological psychiatry. 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A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability

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