Dataset Information

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

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?

SUBMITTER: Te Riele AS

PROVIDER: S-EPMC5220677 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Te Riele Anneline S J M AS Agullo-Pascual Esperanza E James Cynthia A CA Leo-Macias Alejandra A Cerrone Marina M Zhang Mingliang M Lin Xianming X Lin Bin B Sobreira Nara L NL Amat-Alarcon Nuria N Marsman Roos F RF Murray Brittney B Tichnell Crystal C van der Heijden Jeroen F JF Dooijes Dennis D van Veen Toon A B TA Tandri Harikrishna H Fowler Steven J SJ Hauer Richard N W RN Tomaselli Gordon G van den Berg Maarten P MP Taylor Matthew R G MR Brun Francesca F Sinagra Gianfranco G Wilde Arthur A M AA Mestroni Luisa L Bezzina Connie R CR Calkins Hugh H Peter van Tintelen J J Bu Lei L Delmar Mario M Judge Daniel P DP

Cardiovascular research 20170101 1

<h4>Aims</h4>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<sub>v</sub>1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Na<sub>v</sub>1.5) in ARVD/C.<h4>Methods and results</h4>We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmos ...[more]

PMID: 28069705

Similar Datasets

Project description:Purpose To compare epicardial fat in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) with that in healthy subjects. Materials and Methods In this retrospective study, cardiac CT scans in 44 patients with ARVD/C (mean age, 39 years ± 12; 23 men) were compared with those in 45 control group participants between January 2008 and July 2015. Volumes of intrathoracic adipose tissue, mediastinal adipose tissue (MAT), and total epicardial adipose tissue (EAT) were quantified. EAT was subdivided into three regions-right ventricular (RV) EAT, left ventricular (LV) EAT, and peri-atrial EAT (atrial EAT)-and normalized to MAT for all regions. Logistic regression and receiver operating characteristic analysis were performed to evaluate the association between epicardial fat with the diagnosis of ARVD/C. Results Total EAT volume was higher in patients with ARVD/C than in healthy control group participants (median, 98 mL vs 76 mL, respectively; P = .04). Regionally, LV and RV EAT volumes were higher in patients with ARVD/C than in control group participants, most notably when indexed to MAT (median LV EAT index: 0.49 vs 0.15, respectively; median RV EAT index: 0.91 vs 0.52; P ? .0005 for both). The optimal cutoff for diagnosis of ARVD/C was an LV EAT index of 0.24, with a sensitivity and specificity of 91% and 71%, respectively. Atrial EAT volume and total intrathoracic adipose tissue volume were not different between groups. RV diameter showed a positive correlation with total EAT index and LV EAT index (r = 0.21, P = .05 and r = 0.33, P = .002, respectively). Conclusion Higher amounts of right ventricular and left ventricular epicardial fat are found in hearts with arrhythmogenic right ventricular dysplasia/cardiomyopathy, particularly adjacent to the left ventricle, which correlates with disease severity and helps differentiate patients from healthy subjects. © RSNA, 2018 Online supplemental material is available for this article.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets