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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/20/15089 |
| _version_ | 1797573723988951040 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Anthony Frosio |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T21:13:05Z |
| format | Article |
| id | doaj.art-c45660b02a1f45a285d0553ade3549f8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:13:05Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c45660b02a1f45a285d0553ade3549f82023-11-19T16:41:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124201508910.3390/ijms242015089Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic InsightsAnthony Frosio0Emanuele Micaglio1Ivan Polsinelli2Serena Calamaio3Dario Melgari4Rachele Prevostini5Andrea Ghiroldi6Anna Binda7Paola Carrera8Marco Villa9Flavio Mastrocinque10Silvia Presi11Raffaele Salerno12Antonio Boccellino13Luigi Anastasia14Giuseppe Ciconte15Stefano Ricagno16Carlo Pappone17Ilaria Rivolta18Institute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, Via Cadore, 48, 20900 Monza, ItalyLaboratory of Clinical Molecular Genetics and Cytogenetics, Unit of Genomics for Diagnosis of Human Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyArrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyLaboratory of Clinical Molecular Genetics and Cytogenetics, Unit of Genomics for Diagnosis of Human Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, ItalyFaculty of Medicine and Surgery, Vita-Salute San Raffaele University, Via Olgettina, 58, 20132 Milan, ItalyArrhythmia and Electrophysiology Department, IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyInstitute of Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, 20097 San Donato Milanese, ItalyBrugada 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.https://www.mdpi.com/1422-0067/24/20/15089Brugada syndromesudden cardiac deatharrhythmiassodium channelNav1.5<i>SCN5A</i> |
| spellingShingle | 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 Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights International Journal of Molecular Sciences Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i>SCN5A</i> |
| title | Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights |
| title_full | Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights |
| title_fullStr | Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights |
| title_full_unstemmed | Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights |
| title_short | Unravelling Novel <i>SCN5A</i> Mutations Linked to Brugada Syndrome: Functional, Structural, and Genetic Insights |
| title_sort | unravelling novel i scn5a i mutations linked to brugada syndrome functional structural and genetic insights |
| topic | Brugada syndrome sudden cardiac death arrhythmias sodium channel Nav1.5 <i>SCN5A</i> |
| url | https://www.mdpi.com/1422-0067/24/20/15089 |
| work_keys_str_mv | AT anthonyfrosio unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT emanuelemicaglio unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT ivanpolsinelli unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT serenacalamaio unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT dariomelgari unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT racheleprevostini unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT andreaghiroldi unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT annabinda unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT paolacarrera unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT marcovilla unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT flaviomastrocinque unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT silviapresi unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT raffaelesalerno unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT antonioboccellino unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT luigianastasia unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT giuseppeciconte unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT stefanoricagno unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT carlopappone unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights AT ilariarivolta unravellingnoveliscn5aimutationslinkedtobrugadasyndromefunctionalstructuralandgeneticinsights |