Anneline S J M Te Riele1,2,3, Esperanza Agullo-Pascual4, Cynthia A James1, Alejandra Leo-Macias4, Marina Cerrone4, Mingliang Zhang4, Xianming Lin4, Bin Lin4, Nara L Sobreira5, Nuria Amat-Alarcon1, Roos F Marsman6, Brittney Murray1, Crystal Tichnell1, Jeroen F van der Heijden2, Dennis Dooijes7, Toon A B van Veen8, Harikrishna Tandri1, Steven J Fowler4, Richard N W Hauer2,3, Gordon Tomaselli1, Maarten P van den Berg9, Matthew R G Taylor10, Francesca Brun11, Gianfranco Sinagra11, Arthur A M Wilde6, Luisa Mestroni10, Connie R Bezzina6, Hugh Calkins1, J Peter van Tintelen9,12,13, Lei Bu4,1, Mario Delmar4,1, Daniel P Judge14. 1. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA. 2. Division of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands. 3. Netherlands Heart Institute, Moreelsepark 1, Utrecht, the Netherlands. 4. Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA. 5. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, USA. 6. Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands. 7. Department of Medical Genetics, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands. 8. Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht, the Netherlands. 9. Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands. 10. Cardiovascular Institute and Adult Medical Genetics, University of Colorado Denver, 12605 E 16th Avenue, Aurora, CO, USA. 11. Cardiovascular Department, Ospedali Riuniti and University of Trieste, Via Farneto 3, Trieste, Italy. 12. Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands. 13. Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, the Netherlands. 14. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA; djudge@jhmi.edu mario.delmar@nyumc.org lei.bu@med.nyu.edu.
Abstract
AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. CONCLUSIONS: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. CONCLUSIONS: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy. Published on behalf of the European Society of Cardiology. All rights reserved.
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