We developed a new model of cardiac tissue-specific transgenic-like mice on the basis of AAV gene transfer to test the potential of a combination of a human PKP2 mutation and endurance training to trigger an ARVC-like phenotype.
Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci.
Several mutations in the genes encoding RyR1 and RyR2 have been identified in autosomal dominant diseases of skeletal and cardiac muscle, such as malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2).
Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).
The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2).
Arrhythmogenic right ventricular dysplasia/cardiomyopathy type 2 (ARVD2, OMIM 600996) and stress-induced polymorphic ventricular tachycardia (VTSIP, OMIM 604772) are two cardiac diseases causing juvenile sudden death, both associated with mutations in the RyR2 calcium channel.
High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (<i>CDH2</i>) gene in unrelated genotype-negative patients with ARVC.
Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC.
This comprehensive proteogenomics profiling study reveals that an activation of C/EBPα, along with the upregulation of its lipogenesis targets, accounts for lipid storage and acts as a hallmark of ARVC.
Finally, we screened the members of the ARVD family for mutations and identified two DNA sequence variants in the protein-coding exons of NAPOR, neither of which was responsible for ARVD.
Finally, we screened the members of the ARVD family for mutations and identified two DNA sequence variants in the protein-coding exons of NAPOR, neither of which was responsible for ARVD.
We hypothesized that mutations in the genes encoding β-catenin (CTNNB1), α-T-catenin (CTNNA3), and PERP (PERP)-all important structural proteins located at the intercalated disc-were involved in the pathogenesis of ARVC.
As of April 20, 2014, we have updated the ARVD/C database into the ARVD/C database to contain more than 1,400 variants in 12 ACM-related genes (PKP2, DSP, DSC2, DSG2, JUP, TGFB3, TMEM43, LMNA, DES, TTN, PLN, CTNNA3) as reported in more than 160 references.
This novel model of ARVC demonstrates for the first time how plakoglobin affects β-catenin activity in the heart and its implications for disease pathogenesis.
Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity in cardiogenic conditions; yet, these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions.
We hypothesized that mutations in the genes encoding β-catenin (CTNNB1), α-T-catenin (CTNNA3), and PERP (PERP)-all important structural proteins located at the intercalated disc-were involved in the pathogenesis of ARVC.
We examined plakophilin-2, desmoglein-2, desmocollin-2, plakoglobin and β-catenin protein expression levels from seven independent ARVD/C heart samples compared to two ischemic, five dilated cardiomyopathy and one healthy heart sample as controls.