Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis

Anneline S.J.M. Te Riele, Esperanza Agullo-Pascual, Cynthia A. James, Alejandra Leo-Macias, Marina Cerrone, Mingliang Zhang, Xianming Lin, Bin Lin, Eli Rothenberg, Nara L. Sobreira, Nuria Amat-Alarcon, Roos F. Marsman, Brittney Murray, Crystal Tichnell, Jeroen F. Van Der Heijden, Dennis Dooijes, Toon A.B. Van Veen, Harikrishna Tandri, Steven J. Fowler, Richard N.W. HauerGordon Tomaselli, Maarten P. Van Den Berg, Matthew R.G. Taylor, Francesca Brun, Gianfranco Sinagra, Arthur A.M. Wilde, Luisa Mestroni, Connie R. Bezzina, Hugh Calkins, J. Peter Van Tintelen, Lei Bu, Mario Delmar, Daniel P. Judge

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)102-111
Number of pages10
JournalCardiovascular research
Issue number1
StatePublished - Jan 1 2017
Externally publishedYes


  • Arrhythmogenic right ventricular cardiomyopathy
  • Cardiomyopathy
  • Genetics
  • Ion channel electrophysiology
  • SCN5A

ASJC Scopus subject areas

  • General Medicine


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