期刊
CARDIOVASCULAR RESEARCH
卷 113, 期 1, 页码 102-111出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvw234
关键词
Arrhythmogenic right ventricular cardiomyopathy; SCN5A; Genetics; Cardiomyopathy; Ion channel electrophysiology
资金
- Dutch Heart Foundation [2015T058]
- Interuniversity Cardiology Institute of the Netherlands [06901]
- Netherlands Cardiovascular Research Initiative of the Dutch Heart Foundation
- Dutch Federation of University Medical Centres
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Sciences [CVON 2012-10]
- American Heart Association [SDG 14SDG15850014, 15POST25550087]
- National Institutes of Health [U54HG006542, UL1TR001079, R01HL116906, UL1RR025780, R01HL69071, K23JL067915, R01HL109209, HL106632-04, GM57691-17]
- CRTrieste and Generali Assicurazioni Foundations
- Children's Cardiomyopathy Foundation
- Bogle Foundation
- Healing Hearts Foundation
- Campanella family
- Patrick J. Harrison Family
- Dr Francis P. Chiaramonte Private Foundation
- Peter French Memorial Foundation
- Wilmerding Endowments
- Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins
- St Jude Medical Foundation
- Medtronic Inc.
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001079, UL1TR001082] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025780] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL116906, R01HL106632, R01HL069071, R01HL109209] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG006542] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM057691] Funding Source: NIH RePORTER
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 Na(v)1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na(v)1.5) 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 Na(v)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. Conclusions Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Na(v)1.5 and N-Cadherin clusters at junctional sites. This suggests that Na(v)1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Na(v)1.5 dysfunction causes cardiomyopathy.
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