Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights

Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature i...
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Autor*in:	Anthony Frosio [verfasserIn] Emanuele Micaglio [verfasserIn] Ivan Polsinelli [verfasserIn] Serena Calamaio [verfasserIn] Dario Melgari [verfasserIn] Rachele Prevostini [verfasserIn] Andrea Ghiroldi [verfasserIn] Anna Binda [verfasserIn] Paola Carrera [verfasserIn] Marco Villa [verfasserIn] Flavio Mastrocinque [verfasserIn] Silvia Presi [verfasserIn] Raffaele Salerno [verfasserIn] Antonio Boccellino [verfasserIn] Luigi Anastasia [verfasserIn] Giuseppe Ciconte [verfasserIn] Stefano Ricagno [verfasserIn] Carlo Pappone [verfasserIn] Ilaria Rivolta [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 24(2023), 15089, p 15089
Übergeordnetes Werk:	volume:24 ; year:2023 ; number:15089, p 15089

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

DOI / URN:	10.3390/ijms242015089

Katalog-ID:	DOAJ093133995

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520			\|a Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
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allfields	10.3390/ijms242015089 doi (DE-627)DOAJ093133995 (DE-599)DOAJc45660b02a1f45a285d0553ade3549f8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Anthony Frosio verfasserin aut Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions. Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i< Biology (General) Chemistry Emanuele Micaglio verfasserin aut Ivan Polsinelli verfasserin aut Serena Calamaio verfasserin aut Dario Melgari verfasserin aut Rachele Prevostini verfasserin aut Andrea Ghiroldi verfasserin aut Anna Binda verfasserin aut Paola Carrera verfasserin aut Marco Villa verfasserin aut Flavio Mastrocinque verfasserin aut Silvia Presi verfasserin aut Raffaele Salerno verfasserin aut Antonio Boccellino verfasserin aut Luigi Anastasia verfasserin aut Giuseppe Ciconte verfasserin aut Stefano Ricagno verfasserin aut Carlo Pappone verfasserin aut Ilaria Rivolta verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 15089, p 15089 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:15089, p 15089 https://doi.org/10.3390/ijms242015089 kostenfrei https://doaj.org/article/c45660b02a1f45a285d0553ade3549f8 kostenfrei https://www.mdpi.com/1422-0067/24/20/15089 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 24 2023 15089, p 15089
spelling	10.3390/ijms242015089 doi (DE-627)DOAJ093133995 (DE-599)DOAJc45660b02a1f45a285d0553ade3549f8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Anthony Frosio verfasserin aut Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions. Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i< Biology (General) Chemistry Emanuele Micaglio verfasserin aut Ivan Polsinelli verfasserin aut Serena Calamaio verfasserin aut Dario Melgari verfasserin aut Rachele Prevostini verfasserin aut Andrea Ghiroldi verfasserin aut Anna Binda verfasserin aut Paola Carrera verfasserin aut Marco Villa verfasserin aut Flavio Mastrocinque verfasserin aut Silvia Presi verfasserin aut Raffaele Salerno verfasserin aut Antonio Boccellino verfasserin aut Luigi Anastasia verfasserin aut Giuseppe Ciconte verfasserin aut Stefano Ricagno verfasserin aut Carlo Pappone verfasserin aut Ilaria Rivolta verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 15089, p 15089 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:15089, p 15089 https://doi.org/10.3390/ijms242015089 kostenfrei https://doaj.org/article/c45660b02a1f45a285d0553ade3549f8 kostenfrei https://www.mdpi.com/1422-0067/24/20/15089 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 24 2023 15089, p 15089
allfields_unstemmed	10.3390/ijms242015089 doi (DE-627)DOAJ093133995 (DE-599)DOAJc45660b02a1f45a285d0553ade3549f8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Anthony Frosio verfasserin aut Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions. Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i< Biology (General) Chemistry Emanuele Micaglio verfasserin aut Ivan Polsinelli verfasserin aut Serena Calamaio verfasserin aut Dario Melgari verfasserin aut Rachele Prevostini verfasserin aut Andrea Ghiroldi verfasserin aut Anna Binda verfasserin aut Paola Carrera verfasserin aut Marco Villa verfasserin aut Flavio Mastrocinque verfasserin aut Silvia Presi verfasserin aut Raffaele Salerno verfasserin aut Antonio Boccellino verfasserin aut Luigi Anastasia verfasserin aut Giuseppe Ciconte verfasserin aut Stefano Ricagno verfasserin aut Carlo Pappone verfasserin aut Ilaria Rivolta verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 15089, p 15089 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:15089, p 15089 https://doi.org/10.3390/ijms242015089 kostenfrei https://doaj.org/article/c45660b02a1f45a285d0553ade3549f8 kostenfrei https://www.mdpi.com/1422-0067/24/20/15089 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 24 2023 15089, p 15089
allfieldsGer	10.3390/ijms242015089 doi (DE-627)DOAJ093133995 (DE-599)DOAJc45660b02a1f45a285d0553ade3549f8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Anthony Frosio verfasserin aut Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions. Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i< Biology (General) Chemistry Emanuele Micaglio verfasserin aut Ivan Polsinelli verfasserin aut Serena Calamaio verfasserin aut Dario Melgari verfasserin aut Rachele Prevostini verfasserin aut Andrea Ghiroldi verfasserin aut Anna Binda verfasserin aut Paola Carrera verfasserin aut Marco Villa verfasserin aut Flavio Mastrocinque verfasserin aut Silvia Presi verfasserin aut Raffaele Salerno verfasserin aut Antonio Boccellino verfasserin aut Luigi Anastasia verfasserin aut Giuseppe Ciconte verfasserin aut Stefano Ricagno verfasserin aut Carlo Pappone verfasserin aut Ilaria Rivolta verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 15089, p 15089 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:15089, p 15089 https://doi.org/10.3390/ijms242015089 kostenfrei https://doaj.org/article/c45660b02a1f45a285d0553ade3549f8 kostenfrei https://www.mdpi.com/1422-0067/24/20/15089 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 24 2023 15089, p 15089
allfieldsSound	10.3390/ijms242015089 doi (DE-627)DOAJ093133995 (DE-599)DOAJc45660b02a1f45a285d0553ade3549f8 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Anthony Frosio verfasserin aut Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions. Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i< Biology (General) Chemistry Emanuele Micaglio verfasserin aut Ivan Polsinelli verfasserin aut Serena Calamaio verfasserin aut Dario Melgari verfasserin aut Rachele Prevostini verfasserin aut Andrea Ghiroldi verfasserin aut Anna Binda verfasserin aut Paola Carrera verfasserin aut Marco Villa verfasserin aut Flavio Mastrocinque verfasserin aut Silvia Presi verfasserin aut Raffaele Salerno verfasserin aut Antonio Boccellino verfasserin aut Luigi Anastasia verfasserin aut Giuseppe Ciconte verfasserin aut Stefano Ricagno verfasserin aut Carlo Pappone verfasserin aut Ilaria Rivolta verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 24(2023), 15089, p 15089 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:24 year:2023 number:15089, p 15089 https://doi.org/10.3390/ijms242015089 kostenfrei https://doaj.org/article/c45660b02a1f45a285d0553ade3549f8 kostenfrei https://www.mdpi.com/1422-0067/24/20/15089 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 24 2023 15089, p 15089
language	English
source	In International Journal of Molecular Sciences 24(2023), 15089, p 15089 volume:24 year:2023 number:15089, p 15089
sourceStr	In International Journal of Molecular Sciences 24(2023), 15089, p 15089 volume:24 year:2023 number:15089, p 15089
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i< Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Anthony Frosio @@aut@@ Emanuele Micaglio @@aut@@ Ivan Polsinelli @@aut@@ Serena Calamaio @@aut@@ Dario Melgari @@aut@@ Rachele Prevostini @@aut@@ Andrea Ghiroldi @@aut@@ Anna Binda @@aut@@ Paola Carrera @@aut@@ Marco Villa @@aut@@ Flavio Mastrocinque @@aut@@ Silvia Presi @@aut@@ Raffaele Salerno @@aut@@ Antonio Boccellino @@aut@@ Luigi Anastasia @@aut@@ Giuseppe Ciconte @@aut@@ Stefano Ricagno @@aut@@ Carlo Pappone @@aut@@ Ilaria Rivolta @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	316340715
id	DOAJ093133995
language_de	englisch
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callnumber-first	Q - Science
author	Anthony Frosio
spellingShingle	Anthony Frosio misc QH301-705.5 misc QD1-999 misc Brugada syndrome misc sudden cardiac death misc arrhythmias misc sodium channel misc Nav1.5 misc <i<SCN5A</i< misc Biology (General) misc Chemistry Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
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topic_title	QH301-705.5 QD1-999 Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i<SCN5A</i<
topic	misc QH301-705.5 misc QD1-999 misc Brugada syndrome misc sudden cardiac death misc arrhythmias misc sodium channel misc Nav1.5 misc <i<SCN5A</i< misc Biology (General) misc Chemistry
topic_unstemmed	misc QH301-705.5 misc QD1-999 misc Brugada syndrome misc sudden cardiac death misc arrhythmias misc sodium channel misc Nav1.5 misc <i<SCN5A</i< misc Biology (General) misc Chemistry
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title	Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
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title_full	Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
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author_browse	Anthony Frosio Emanuele Micaglio Ivan Polsinelli Serena Calamaio Dario Melgari Rachele Prevostini Andrea Ghiroldi Anna Binda Paola Carrera Marco Villa Flavio Mastrocinque Silvia Presi Raffaele Salerno Antonio Boccellino Luigi Anastasia Giuseppe Ciconte Stefano Ricagno Carlo Pappone Ilaria Rivolta
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author-letter	Anthony Frosio
doi_str_mv	10.3390/ijms242015089
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title_sort	unravelling novel <i<scn5a</i< mutations linked to brugada syndrome: functional, structural, and genetic insights
callnumber	QH301-705.5
title_auth	Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
abstract	Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
abstractGer	Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
abstract_unstemmed	Brugada Syndrome (BrS) is a rare inherited cardiac arrhythmia causing potentially fatal ventricular tachycardia or fibrillation, mainly occurring during rest or sleep in young individuals without heart structural issues. It increases the risk of sudden cardiac death, and its characteristic feature is an abnormal ST segment elevation on the ECG. While BrS has diverse genetic origins, a subset of cases can be conducted to mutations in the <i<SCN5A</i< gene, which encodes for the Nav1.5 sodium channel. Our study focused on three novel <i<SCN5A</i< mutations (p.A344S, p.N347K, and p.D349N) found in unrelated BrS families. Using patch clamp experiments, we found that these mutations disrupted sodium currents: p.A344S reduced current density, while p.N347K and p.D349N completely abolished it, leading to altered voltage dependence and inactivation kinetics when co-expressed with normal channels. We also explored the effects of mexiletine treatment, which can modulate ion channel function. Interestingly, the p.N347K and p.D349N mutations responded well to the treatment, rescuing the current density, while p.A344S showed a limited response. Structural analysis revealed these mutations were positioned in key regions of the channel, impacting its stability and function. This research deepens our understanding of BrS by uncovering the complex relationship between genetic mutations, ion channel behavior, and potential therapeutic interventions.
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title_short	Unravelling Novel <i<SCN5A</i< Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights
url	https://doi.org/10.3390/ijms242015089 https://doaj.org/article/c45660b02a1f45a285d0553ade3549f8 https://www.mdpi.com/1422-0067/24/20/15089 https://doaj.org/toc/1661-6596 https://doaj.org/toc/1422-0067
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