{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:46:14Z","timestamp":1784205974843,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T00:00:00Z","timestamp":1623888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2017"],"award-info":[{"award-number":["PRIN 2017"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005362","name":"Universita degli Studi di Bari Aldo Moro","doi-asserted-by":"publisher","award":["Fondi Ateneo 2017-2018"],"award-info":[{"award-number":["Fondi Ateneo 2017-2018"]}],"id":[{"id":"10.13039\/501100005362","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background. Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by \u201ccoved type\u201d ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20\u201330% 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 SCN5A 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.<\/jats:p>","DOI":"10.3390\/ijms22126513","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T11:20:26Z","timestamp":1623928826000},"page":"6513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Functional Characterization of Two Novel Mutations in SCN5A Associated with Brugada Syndrome Identified in Italian Patients"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2110-8961","authenticated-orcid":false,"given":"Cristina","family":"Balla","sequence":"first","affiliation":[{"name":"Cardiological Center, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Conte","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3099-0100","authenticated-orcid":false,"given":"Rita","family":"Selvatici","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8450-1010","authenticated-orcid":false,"given":"Ren\u00e8 Massimiliano","family":"Marsano","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2839-0130","authenticated-orcid":false,"given":"Andrea","family":"Gerbino","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Farn\u00e8","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4484-2907","authenticated-orcid":false,"given":"Rikard","family":"Blunck","sequence":"additional","affiliation":[{"name":"Department of Physics, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0667-7616","authenticated-orcid":false,"given":"Francesco","family":"Vitali","sequence":"additional","affiliation":[{"name":"Cardiological Center, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annarita","family":"Armaroli","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7849-1319","authenticated-orcid":false,"given":"Alessandro","family":"Brieda","sequence":"additional","affiliation":[{"name":"Cardiological Center, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Liantonio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-7341","authenticated-orcid":false,"given":"Annamaria","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Ferlini","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Rapezzi","sequence":"additional","affiliation":[{"name":"Cardiological Center, University of Ferrara, 44121 Ferrara, Italy"},{"name":"Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5285-7140","authenticated-orcid":false,"given":"Matteo","family":"Bertini","sequence":"additional","affiliation":[{"name":"Cardiological Center, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Gualandi","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9140-5350","authenticated-orcid":false,"given":"Paola","family":"Imbrici","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Drug Sciences, University of Bari \u201cAldo Moro\u201d, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.jacc.2018.06.037","article-title":"Present Status of Brugada Syndrome: JACC State-of-the-Art Review","volume":"72","author":"Brugada","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","first-page":"100454","article-title":"Update on Brugada Syndrome","volume":"23","author":"Coppola","year":"2019","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.ijcard.2017.11.113","article-title":"Prevalence of spontaneous Brugada ECG pattern recorded at standard intercostal leads: A meta-analysis","volume":"254","author":"Shi","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Garcia-Elias, A., and Benito, B. (2018). Ion Channel Disorders and Sudden Cardiac Death. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030692"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/humu.23730","article-title":"Genetic interpretation and clinical translation of minor genes related to Brugada syndrome","volume":"40","author":"Campuzano","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"652027","DOI":"10.3389\/fcvm.2021.652027","article-title":"Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification","volume":"8","author":"Monasky","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1146\/annurev-pharmtox-010818-021757","article-title":"Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels","volume":"60","author":"Catterall","year":"2020","journal-title":"Ann. Rev. Pharmacol. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.hrthm.2009.09.069","article-title":"An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing","volume":"7","author":"Kapplinger","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1111\/jce.13740","article-title":"Systematic re-evaluation of SCN5A variants associated with Brugada syndrome","volume":"30","author":"Denham","year":"2019","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jacep.2018.03.006","article-title":"Clinical Spectrum of SCN5A Mutations: Long QT Syndrome, Brugada Syndrome, and Cardiomyopathy","volume":"4","author":"Wilde","year":"2018","journal-title":"JACC Clin. Electrophysiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1161\/CIRCULATIONAHA.117.027983","article-title":"Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands With Brugada Syndrome: A Japanese Multicenter Registry","volume":"135","author":"Yamagata","year":"2017","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.hrthm.2008.11.009","article-title":"Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies","volume":"6","author":"Meregalli","year":"2009","journal-title":"Heart Rhythm"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1111\/pace.13087","article-title":"Infant sudden death: Mutations responsible for impaired Nav1.5 channel trafficking and function","volume":"40","author":"Gando","year":"2017","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ijcard.2017.09.010","article-title":"SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers","volume":"266","author":"Amin","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cpcardiol.2015.06.002","article-title":"Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects","volume":"41","author":"Antzelevitch","year":"2016","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"B61","DOI":"10.1093\/eurheartj\/suz028","article-title":"Epicardial ablation in genetic cardiomyopathies: A new frontier","volume":"21","author":"Pappone","year":"2019","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.ccep.2017.07.005","article-title":"Channelopathies as Causes of Sudden Cardiac Death","volume":"9","author":"Schwartz","year":"2017","journal-title":"Card. Electrophysiol. Clin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1111\/jce.13774","article-title":"SCN5A variants in Brugada syndrome: True, true false, or false true","volume":"30","author":"Walsh","year":"2019","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1159\/000471792","article-title":"Mutation Load of Multiple Ion Channel Gene Mutations in Brugada Syndrome","volume":"137","author":"Gualandi","year":"2017","journal-title":"Cardiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1161\/CIRCULATIONAHA.118.035954","article-title":"Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders","volume":"140","author":"Cerrone","year":"2019","journal-title":"Circulation"},{"key":"ref_21","first-page":"3925","article-title":"Modifier genes for sudden cardiac death","volume":"39","author":"Schwartz","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/cge.13552","article-title":"Brugada syndrome with SCN5A mutations exhibits more pronounced electrophysiological defects and more severe prognosis: A meta-analysis","volume":"97","author":"Chen","year":"2020","journal-title":"Clin. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.hrthm.2012.10.025","article-title":"p.D1690N Nav1.5 rescues p.G1748D mutation gating defects in a compound heterozygous Brugada syndrome patient","volume":"10","author":"Barana","year":"2013","journal-title":"Heart Rhythm"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cell.2019.11.041","article-title":"Structure of the Cardiac Sodium Channel","volume":"180","author":"Jiang","year":"2020","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.yjmcc.2016.01.014","article-title":"A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias","volume":"92","author":"Wang","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1038\/s41467-017-02262-0","article-title":"Voltage-gated sodium channels assemble and gate as dimers","volume":"8","author":"Clatot","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"H1250","DOI":"10.1152\/ajpheart.00721.2017","article-title":"Mutant voltage-gated Na+ channels can exert a dominant negative effect through coupled gating","volume":"315","author":"Clatot","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cardiores.2004.01.022","article-title":"A Trafficking Defective, Brugada Syndrome-Causing SCN5A Mutation Rescued by Drugs","volume":"62","author":"Valdivia","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"H1822","DOI":"10.1152\/ajpheart.00101.2006","article-title":"Partial expression defect for the SCN5A missense mutation G1406R depends on splice variant background Q1077 and rescue by mexiletine","volume":"291","author":"Tan","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.hrthm.2004.07.013","article-title":"Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: Implications for arrhythmogenic susceptibility and Brugada\/long QT syndrome genetic testing","volume":"1","author":"Ackerman","year":"2004","journal-title":"Heart Rhythm"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.hrthm.2019.11.027","article-title":"Age at diagnosis of Brugada syndrome: Influence on clinical characteristics and risk of arrhythmia","volume":"17","author":"Minier","year":"2020","journal-title":"Heart Rhythm"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1093\/eurheartj\/ehaa942","article-title":"Brugada syndrome genetics is associated with phenotype severity","volume":"42","author":"Ciconte","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cjca.2014.03.032","article-title":"Sex differences in cardiac electrophysiology and clinical arrhythmias: Epidemiology, therapeutics, and mechanisms","volume":"30","author":"Tadros","year":"2014","journal-title":"Can. J. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1111\/j.1540-8167.2009.01508.x","article-title":"Genetic modulation of brugada syndrome by a common polymorphism","volume":"20","author":"Lizotte","year":"2009","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12929-017-0397-x","article-title":"H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters","volume":"24","author":"Matsumura","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/cvr\/cvr252","article-title":"Biology of cardiac sodium channel Nav1.5 expression","volume":"93","author":"Rook","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1161\/CIRCRESAHA.116.305017","article-title":"Ion channel macromolecular complexes in cardiomyocytes: Roles in sudden cardiac death","volume":"116","author":"Abriel","year":"2015","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/nrcardio.2016.143","article-title":"Pathogenesis and management of Brugada syndrome","volume":"13","author":"Sieira","year":"2016","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2758","DOI":"10.1016\/j.jacc.2018.08.2199","article-title":"Brugada Syndrome: In Search of a Cause","volume":"72","author":"Corrado","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1093\/cvr\/cvaa082","article-title":"Heritable Arrhythmia Syndromes Associated With Abnormal Cardiac Sodium Channel Function: Ionic and Non-Ionic Mechanisms","volume":"116","author":"Rivaud","year":"2020","journal-title":"Cardiovasc. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E101","DOI":"10.1093\/eurheartj\/suaa071","article-title":"Right ventricular electromechanical abnormalities in Brugada syndrome: Is this a cardiomyopathy?","volume":"22","author":"Pappone","year":"2020","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"121","DOI":"10.3389\/fphar.2016.00121","article-title":"Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery","volume":"7","author":"Imbrici","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.phrs.2019.01.004","article-title":"Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate","volume":"141","author":"Farinato","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative protein modelling by satisfaction of spatial restraints","volume":"234","author":"Sali","year":"1993","journal-title":"J. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/cpbi.3","article-title":"Comparative Protein Structure Modeling Using MODELLER","volume":"54","author":"Webb","year":"2016","journal-title":"Curr. Protoc. Bioinform."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6513\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:17:48Z","timestamp":1760163468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6513"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,17]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22126513"],"URL":"https:\/\/doi.org\/10.3390\/ijms22126513","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,17]]}}}