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

TitleMultilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis.
Publication TypeJournal Article
Year of Publication2017
AuthorsRiele, ASJMTe, Agullo-Pascual, E, James, CA, Leo-Macias, A, Cerrone, M, Zhang, M, Lin, X, Lin, B, Sobreira, NL, Amat-Alarcon, N, Marsman, RF, Murray, B, Tichnell, C, van der Heijden, JF, Dooijes, D, van Veen, TAB, Tandri, H, Fowler, SJ, Hauer, RNW, Tomaselli, G, van den Berg, MP, Taylor, MRG, Brun, F, Sinagra, G, Wilde, AAM, Mestroni, L, Bezzina, CR, Calkins, H, J van Tintelen, P, Bu, L, Delmar, M, Judge, DP
JournalCardiovasc Res
Volume113
Issue1
Pagination102-111
Date Published2017 Jan
ISSN1755-3245
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 

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.

DOI10.1093/cvr/cvw234
Alternate JournalCardiovasc. Res.
PubMed ID28069705
PubMed Central IDPMC5220677
Grant ListR01 HL109209 / HL / NHLBI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
UL1 RR025780 / RR / NCRR NIH HHS / United States
R01 GM057691 / GM / NIGMS NIH HHS / United States
R01 HL069071 / HL / NHLBI NIH HHS / United States
UL1 TR001082 / TR / NCATS NIH HHS / United States
R01 HL116906 / HL / NHLBI NIH HHS / United States
R01 HL106632 / HL / NHLBI NIH HHS / United States