{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T18:40:16Z","timestamp":1773081616086,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ricerca Corrente funding"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Brugada Syndrome (BrS) is a genetic heart condition linked to sudden cardiac death. Though the SCN5A gene is primarily associated with BrS, there is a lack of comprehensive studies exploring the connection between SCN5A mutation locations and the clinical presentations of the syndrome. This study aimed to address this gap and gain further understanding of the syndrome. The investigation classified 36 high-risk BrS patients based on SCN5A mutations within the transmembrane\/structured (TD) and intra-domain loops (IDLs) lacking a 3D structure. We characterized the intrinsically disordered regions (IDRs) abundant in IDLs, using bioinformatics tools to predict IDRs and post-translational modifications (PTMs) in NaV1.5. Interestingly, it was found that current predictive tools often underestimate the impacts of mutations in IDLs and disordered regions. Moreover, patients with SCN5A mutations confined to IDL regions\u2014previously deemed \u2018benign\u2019\u2014displayed clinical symptoms similar to those carrying \u2018damaging\u2019 variants. Our research illuminates the difficulty in stratifying patients based on SCN5A mutation locations, emphasizing the vital role of IDLs in the NaV1.5 channel\u2019s functioning and protein interactions. We advocate for caution when using predictive tools for mutation evaluation in these regions and call for the development of improved strategies in accurately assessing BrS risk<\/jats:p>","DOI":"10.3390\/ijms242316658","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T06:06:23Z","timestamp":1700719583000},"page":"16658","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes"],"prefix":"10.3390","volume":"24","author":[{"given":"Adriana","family":"Tarantino","sequence":"first","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"},{"name":"School of Medicine, University Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Ciconte","sequence":"additional","affiliation":[{"name":"School of Medicine, University Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy"},{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2896-7390","authenticated-orcid":false,"given":"Andrea","family":"Ghiroldi","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0902-9136","authenticated-orcid":false,"given":"Flavio","family":"Mastrocinque","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8298-7800","authenticated-orcid":false,"given":"Emanuele","family":"Micaglio","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Boccellino","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Negro","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-2715","authenticated-orcid":false,"given":"Marco","family":"Piccoli","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-5977","authenticated-orcid":false,"given":"Federica","family":"Cirillo","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Vicedomini","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Santinelli","sequence":"additional","affiliation":[{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luigi","family":"Anastasia","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"},{"name":"School of Medicine, University Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Pappone","sequence":"additional","affiliation":[{"name":"School of Medicine, University Vita-Salute San Raffaele, Via Olgettina 58, 20132 Milan, Italy"},{"name":"Arrhythmology Department, IRCCS Policlinico San Donato, Piazza Malan 2, San Donato Milanese, 20097 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.joa.2016.07.012","article-title":"Genetics of Brugada syndrome","volume":"32","author":"Juang","year":"2016","journal-title":"J. Arrhythmia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e5643","DOI":"10.1097\/MD.0000000000005643","article-title":"A meta-analytic review of prevalence for Brugada ECG patterns and the risk for death","volume":"95","author":"Quan","year":"2016","journal-title":"Medicine"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Monasky, M.M., Micaglio, E., Ciconte, G., and Pappone, C. (2020). Brugada Syndrome: Oligogenic or Mendelian Disease?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051687"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1161\/CIRCULATIONAHA.118.035070","article-title":"Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome","volume":"138","author":"Hosseini","year":"2018","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/j.hrthm.2018.03.033","article-title":"Copy number variations of SCN5A in Brugada syndrome","volume":"15","author":"Sonoda","year":"2018","journal-title":"Heart Rhythm."},{"key":"ref_6","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_7","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_8","doi-asserted-by":"crossref","first-page":"609733","DOI":"10.3389\/fphys.2020.609733","article-title":"Life Cycle of the Cardiac Voltage-Gated Sodium Channel NaV1.5","volume":"11","author":"Dong","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_9","unstructured":"Terjung, R. (2011). Comprehensive Physiology, Wiley. [1st ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Colak, R., Kim, T., Michaut, M., Sun, M., Irimia, M., Bellay, J., Myers, C.L., Blencowe, B.J., and Kim, P.M. (2013). Distinct Types of Disorder in the Human Proteome: Functional Implications for Alternative Splicing. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003030"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1073\/pnas.1516277113","article-title":"Cryptic sequence features within the disordered protein p27Kip1 regulate cell cycle signaling","volume":"113","author":"Das","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4075","DOI":"10.1007\/s00018-016-2283-1","article-title":"A structural perspective of RNA recognition by intrinsically disordered proteins","volume":"73","author":"Basu","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.pbiomolbio.2015.06.004","article-title":"Targeting protein\u2013protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs)","volume":"119","author":"Sammak","year":"2015","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/j.jmb.2007.02.033","article-title":"Intrinsically disordered regions of human plasma membrane proteins preferentially occur in the cytoplasmic segment","volume":"368","author":"Minezaki","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S1093-3263(00)00138-8","article-title":"Intrinsically disordered protein","volume":"19","author":"Dunker","year":"2001","journal-title":"J. Mol. Graph. Model."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/pro.2207","article-title":"Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding: Exploring the Binding Diversity of IDPs","volume":"22","author":"Hsu","year":"2013","journal-title":"Protein Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Owen, I., and Shewmaker, F. (2019). The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215501"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1039\/C1MB05251A","article-title":"Disease mutations in disordered regions\u2014Exception to the rule?","volume":"8","author":"Vacic","year":"2012","journal-title":"Mol. BioSyst."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Goretzki, B., Guhl, C., Tebbe, F., Harder, J.-M., and Hellmich, U.A. (2021). Unstructural Biology of TRP Ion Channels: The Role of Intrinsically Disordered Regions in Channel Function and Regulation. J. Mol. Biol., 433.","DOI":"10.1016\/j.jmb.2021.166931"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0022-2836(02)00969-5","article-title":"Intrinsic Disorder in Cell-signaling and Cancer-associated Proteins","volume":"323","author":"Iakoucheva","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1101\/gr.176601","article-title":"Predicting deleterious amino acid substitutions","volume":"11","author":"Ng","year":"2001","journal-title":"Genome Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e24157","DOI":"10.4161\/idp.24157","article-title":"What\u2019s in a name? Why these proteins are intrinsically disordered: Why these proteins are intrinsically disordered","volume":"1","author":"Dunker","year":"2013","journal-title":"Intrinsically Disord. Proteins"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kirilyuk, A., Shimoji, M., Catania, J., Sahu, G., Pattabiraman, N., Giordano, A., Albanese, C., Mocchetti, I., Toretsky, J.A., and Uversky, V.N. (2012). An Intrinsically Disordered Region of the Acetyltransferase p300 with Similarity to Prion-Like Domains Plays a Role in Aggregation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048243"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1038\/srep02035","article-title":"Intrinsic Disorder in PTEN and its Interactome Confers Structural Plasticity and Functional Versatility","volume":"3","author":"Malaney","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"158","DOI":"10.3389\/fgene.2018.00158","article-title":"Intrinsic Disorder and Posttranslational Modifications: The Darker Side of the Biological Dark Matter","volume":"9","author":"Darling","year":"2018","journal-title":"Front. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1016\/j.str.2013.08.001","article-title":"From Sequence and Forces to Structure, Function, and Evolution of Intrinsically Disordered Proteins","volume":"21","author":"Mittag","year":"2013","journal-title":"Structure"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H431","DOI":"10.1152\/ajpheart.00306.2013","article-title":"Post-translational modifications of the cardiac Na channel: Contribution of CaMKII-dependent phosphorylation to acquired arrhythmias","volume":"305","author":"Herren","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1002\/ajmg.b.32431","article-title":"The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies","volume":"171","author":"Schuch","year":"2016","journal-title":"Am. J. Med. Genet. Part. B Neuropsychiatr. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1146\/annurev.biophys.37.032807.125924","article-title":"Intrinsically Disordered Proteins in Human Diseases: Introducing the D2 Concept","volume":"37","author":"Uversky","year":"2008","journal-title":"Annu. Rev. Biophys."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Vacic, V., Markwick, P.R., Oldfield, C.J., Zhao, X., Haynes, C., Uversky, V.N., and Iakoucheva, L.M. (2012). Disease-associated mutations disrupt functionally important regions of intrinsic protein disorder. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002709"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1016\/j.cell.2020.11.050","article-title":"Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations","volume":"183","author":"Tsang","year":"2020","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1152\/physiolgenomics.00198.2010","article-title":"The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current","volume":"43","author":"Cheng","year":"2011","journal-title":"Physiol. Genom."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"e202012722","DOI":"10.1085\/jgp.202012722","article-title":"Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation","volume":"153","author":"Nathan","year":"2021","journal-title":"J. Gen. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1093\/eurheartj\/ehac262","article-title":"2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death","volume":"43","author":"Zeppenfeld","year":"2022","journal-title":"Eur. Heart. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e005053","DOI":"10.1161\/CIRCEP.117.005053","article-title":"Electrical Substrate Elimination in 135 Consecutive Patients With Brugada Syndrome","volume":"10","author":"Pappone","year":"2017","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1016\/j.jacc.2018.02.022","article-title":"Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome","volume":"71","author":"Pappone","year":"2018","journal-title":"J. Am. Coll. 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