Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis
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 Na 1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the...
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| Published in | Cardiovascular research Vol. 113; no. 1; pp. 102 - 111 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
Oxford University Press
01.01.2017
|
| Series | Editor's Choice |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0008-6363 1755-3245 1755-3245 |
| DOI | 10.1093/cvr/cvw234 |
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| Abstract | 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 Na
1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na
1.5) in ARVD/C.
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 Na
1.5 (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.
Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na
1.5 and N-Cadherin clusters at junctional sites. This suggests that Na
1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na
1.5 dysfunction causes cardiomyopathy. |
|---|---|
| AbstractList | 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 Na
1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na
1.5) in ARVD/C.
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 Na
1.5 (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.
Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na
1.5 and N-Cadherin clusters at junctional sites. This suggests that Na
1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na
1.5 dysfunction causes cardiomyopathy. 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.AIMSArrhythmogenic 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.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.METHODS AND RESULTSWe 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.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.CONCLUSIONSAlmost 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. |
| Author | Brun, Francesca Sinagra, Gianfranco Rothenberg, Eli van den Berg, Maarten P. Bezzina, Connie R. Delmar, Mario Murray, Brittney Marsman, Roos F. Calkins, Hugh te Riele, Anneline S.J.M. Zhang, Mingliang Bu, Lei Peter van Tintelen, J. Lin, Bin Sobreira, Nara L. Tichnell, Crystal Dooijes, Dennis Wilde, Arthur A.M. Tandri, Harikrishna Lin, Xianming Mestroni, Luisa van der Heijden, Jeroen F. Judge, Daniel P. Cerrone, Marina Taylor, Matthew R.G. Tomaselli, Gordon van Veen, Toon A.B. James, Cynthia A. Leo-Macias, Alejandra Agullo-Pascual, Esperanza Fowler, Steven J. Amat-Alarcon, Nuria Hauer, Richard N.W. |
| Author_xml | – sequence: 1 givenname: Anneline S.J.M. surname: te Riele fullname: te Riele, Anneline S.J.M. organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA, Division of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands, Netherlands Heart Institute, Moreelsepark 1, Utrecht, the Netherlands – sequence: 2 givenname: Esperanza surname: Agullo-Pascual fullname: Agullo-Pascual, Esperanza organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 3 givenname: Cynthia A. surname: James fullname: James, Cynthia A. organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 4 givenname: Alejandra surname: Leo-Macias fullname: Leo-Macias, Alejandra organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 5 givenname: Marina surname: Cerrone fullname: Cerrone, Marina organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 6 givenname: Mingliang surname: Zhang fullname: Zhang, Mingliang organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 7 givenname: Xianming surname: Lin fullname: Lin, Xianming organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 8 givenname: Bin surname: Lin fullname: Lin, Bin organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 9 givenname: Eli surname: Rothenberg fullname: Rothenberg, Eli organization: Department of Biochemistry and Molecular Pharmacology, NYU-SoM, 522 First Avenue, MSB 3rd Floor, New York, New York 10016, USA – sequence: 10 givenname: Nara L. surname: Sobreira fullname: Sobreira, Nara L. organization: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD, USA – sequence: 11 givenname: Nuria surname: Amat-Alarcon fullname: Amat-Alarcon, Nuria organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 12 givenname: Roos F. surname: Marsman fullname: Marsman, Roos F. organization: Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands – sequence: 13 givenname: Brittney surname: Murray fullname: Murray, Brittney organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 14 givenname: Crystal surname: Tichnell fullname: Tichnell, Crystal organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 15 givenname: Jeroen F. surname: van der Heijden fullname: van der Heijden, Jeroen F. organization: Division of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands – sequence: 16 givenname: Dennis surname: Dooijes fullname: Dooijes, Dennis organization: Department of Medical Genetics, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands – sequence: 17 givenname: Toon A.B. surname: van Veen fullname: van Veen, Toon A.B. organization: Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht, the Netherlands – sequence: 18 givenname: Harikrishna surname: Tandri fullname: Tandri, Harikrishna organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 19 givenname: Steven J. surname: Fowler fullname: Fowler, Steven J. organization: Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 20 givenname: Richard N.W. surname: Hauer fullname: Hauer, Richard N.W. organization: Division of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, the Netherlands, Netherlands Heart Institute, Moreelsepark 1, Utrecht, the Netherlands – sequence: 21 givenname: Gordon surname: Tomaselli fullname: Tomaselli, Gordon organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 22 givenname: Maarten P. surname: van den Berg fullname: van den Berg, Maarten P. organization: Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands – sequence: 23 givenname: Matthew R.G. surname: Taylor fullname: Taylor, Matthew R.G. organization: Cardiovascular Institute and Adult Medical Genetics, University of Colorado Denver, 12605 E 16th Avenue, Aurora, CO, USA – sequence: 24 givenname: Francesca surname: Brun fullname: Brun, Francesca organization: Cardiovascular Department, Ospedali Riuniti and University of Trieste, Via Farneto 3, Trieste, Italy – sequence: 25 givenname: Gianfranco surname: Sinagra fullname: Sinagra, Gianfranco organization: Cardiovascular Department, Ospedali Riuniti and University of Trieste, Via Farneto 3, Trieste, Italy – sequence: 26 givenname: Arthur A.M. surname: Wilde fullname: Wilde, Arthur A.M. organization: Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands – sequence: 27 givenname: Luisa surname: Mestroni fullname: Mestroni, Luisa organization: Cardiovascular Institute and Adult Medical Genetics, University of Colorado Denver, 12605 E 16th Avenue, Aurora, CO, USA – sequence: 28 givenname: Connie R. surname: Bezzina fullname: Bezzina, Connie R. organization: Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Meibergdreef 9, Amsterdam, the Netherlands – sequence: 29 givenname: Hugh surname: Calkins fullname: Calkins, Hugh organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA – sequence: 30 givenname: J. surname: Peter van Tintelen fullname: Peter van Tintelen, J. organization: Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen, the Netherlands, Department of Clinical Genetics, Academic Medical Center Amsterdam, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands, Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, the Netherlands – sequence: 31 givenname: Lei surname: Bu fullname: Bu, Lei organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA, Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 32 givenname: Mario surname: Delmar fullname: Delmar, Mario organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA, Leon H. Charney Division of Cardiology, New York University School of Medicine, 550 First Avenue, New York, NY, USA – sequence: 33 givenname: Daniel P. surname: Judge fullname: Judge, Daniel P. organization: Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, 1800 Orleans Street, Baltimore, MD, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28069705$$D View this record in MEDLINE/PubMed |
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| Keywords | Genetics SCN5A Arrhythmogenic right ventricular cardiomyopathy Ion channel electrophysiology Cardiomyopathy |
| Language | English |
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| SubjectTerms | Adult Antigens, CD - metabolism Arrhythmogenic Right Ventricular Dysplasia - diagnostic imaging Arrhythmogenic Right Ventricular Dysplasia - genetics Arrhythmogenic Right Ventricular Dysplasia - metabolism Cadherins - metabolism Cell Differentiation CRISPR-Cas Systems DNA Mutational Analysis Electrocardiography Exome Female Gene Editing - methods Gene Frequency Genetic Predisposition to Disease Genome-Wide Association Study HEK293 Cells Humans Induced Pluripotent Stem Cells - metabolism Magnetic Resonance Imaging Male Membrane Potentials Middle Aged Multilevel Analysis Mutation, Missense Myocytes, Cardiac - metabolism NAV1.5 Voltage-Gated Sodium Channel - genetics NAV1.5 Voltage-Gated Sodium Channel - metabolism Netherlands Original Phenotype Sodium - metabolism Transfection United States Young Adult |
| Title | Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis |
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