Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients
Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The <i>SCN5A</i> gene, enc...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/12/6513 |
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| author | Cristina Balla Elena Conte Rita Selvatici Renè Massimiliano Marsano Andrea Gerbino Marianna Farnè Rikard Blunck Francesco Vitali Annarita Armaroli Alessandro Brieda Antonella Liantonio Annamaria De Luca Alessandra Ferlini Claudio Rapezzi Matteo Bertini Francesca Gualandi Paola Imbrici |
| author_facet | Cristina Balla Elena Conte Rita Selvatici Renè Massimiliano Marsano Andrea Gerbino Marianna Farnè Rikard Blunck Francesco Vitali Annarita Armaroli Alessandro Brieda Antonella Liantonio Annamaria De Luca Alessandra Ferlini Claudio Rapezzi Matteo Bertini Francesca Gualandi Paola Imbrici |
| author_sort | Cristina Balla |
| collection | DOAJ |
| description | Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The <i>SCN5A</i> gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel <i>SCN5A</i> mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention. |
| first_indexed | 2024-03-10T10:19:55Z |
| format | Article |
| id | doaj.art-d63706f84d6648c3a96a3fc369ab63cb |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:19:55Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d63706f84d6648c3a96a3fc369ab63cb2023-11-22T00:34:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012212651310.3390/ijms22126513Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian PatientsCristina Balla0Elena Conte1Rita Selvatici2Renè Massimiliano Marsano3Andrea Gerbino4Marianna Farnè5Rikard Blunck6Francesco Vitali7Annarita Armaroli8Alessandro Brieda9Antonella Liantonio10Annamaria De Luca11Alessandra Ferlini12Claudio Rapezzi13Matteo Bertini14Francesca Gualandi15Paola Imbrici16Cardiological Center, University of Ferrara, 44121 Ferrara, ItalyDepartment of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Biology, University of Bari “Aldo Moro”, 70125 Bari, ItalyDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “Aldo Moro”, 70125 Bari, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Physics, Université de Montréal, Montréal, QC H3C 3J7, CanadaCardiological Center, University of Ferrara, 44121 Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, ItalyCardiological Center, University of Ferrara, 44121 Ferrara, ItalyDepartment of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, ItalyDepartment of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, ItalyCardiological Center, University of Ferrara, 44121 Ferrara, ItalyCardiological Center, University of Ferrara, 44121 Ferrara, ItalyUnit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, 70125 Bari, ItalyBackground. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by “coved type” ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The <i>SCN5A</i> gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20–30% of BrS cases and is considered clinically relevant. Methods. Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel <i>SCN5A</i> mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. Results. Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. Conclusions. Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.https://www.mdpi.com/1422-0067/22/12/6513Brugada syndrome<i>SCN5A</i>electrophysiologyNa<sup>+</sup> current |
| spellingShingle | Cristina Balla Elena Conte Rita Selvatici Renè Massimiliano Marsano Andrea Gerbino Marianna Farnè Rikard Blunck Francesco Vitali Annarita Armaroli Alessandro Brieda Antonella Liantonio Annamaria De Luca Alessandra Ferlini Claudio Rapezzi Matteo Bertini Francesca Gualandi Paola Imbrici Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients International Journal of Molecular Sciences Brugada syndrome <i>SCN5A</i> electrophysiology Na<sup>+</sup> current |
| title | Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients |
| title_full | Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients |
| title_fullStr | Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients |
| title_full_unstemmed | Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients |
| title_short | Functional Characterization of Two Novel Mutations in <i>SCN5A</i> Associated with Brugada Syndrome Identified in Italian Patients |
| title_sort | functional characterization of two novel mutations in i scn5a i associated with brugada syndrome identified in italian patients |
| topic | Brugada syndrome <i>SCN5A</i> electrophysiology Na<sup>+</sup> current |
| url | https://www.mdpi.com/1422-0067/22/12/6513 |
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