Genetic Background of Catecholaminergic Polymorphic Ventricular Tachycardia in Japan

Non-ventricular, Clinical, and Functional Features of the RyR2R420Q Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia

“…This mutation, recently reported in 4 unrelated patients, lacks clinical and functional characterization. 14,32 Remarkably, the residue 420 is highly conserved across species 32 and behaves as a hot spot, given that different substitutions have been described at the same point and near it (R420W 3,33-35 and I419F 36,37 RyR2 R420Q shows a higher penetrance than the RyR2 R420W (91% vs 25%), and does not display any feature of arrhythmogenic cardiomyopathy. 33,34 So far, most CPVT mutations in which functional studies have been performed behave as gain-of-function.…”

“…19 Genetic Work-up DNA was obtained from whole blood (relatives) or from paraffin-embedded myocardium (proband). Targeted mutational RyR2 analysis (direct sequencing of exons 3,8,14,15,37,[44][45][46][47][48][49][50]83, 87-105, and adjacent intronic regions, GenBank accession number NM_001035) with an ABI Prism 3100 sequencer (Applied Biosystems) in individual III:10 identified the RyR2 R420Q mutation and exon 14 was sequenced in the remaining relatives (mutation carriers were considered genotype+). Since Andersen Tawil syndrome is characterized by a normal or near-normal QTc, giant U waves and polymorphic exercise-related VA due to mutations in KCNJ2 gene, this gene was also sequenced in CPVT individuals.…”

“…3,[5][6][7][8][9] Mutations usually affect the gene encoding the cardiac ryanodine receptor (RyR2), but other genes have also been involved. [10][11][12][13][14] Abnormal intracellular calcium (Ca 2+ ) handling underlies an increased diastolic Ca 2+ release, delayed after depolarizations and triggered activity, which is the pathophysiological basis of VA in this disease. 3,15 However, the precise mechanisms might differ depending on the specific mutation at the RyR2 protein.…”

Genomic-based diagnosis of arrhythmia disease in a personalized medicine era

“…The genes involved in CPVT mainly involve Ca 2+ homeostasis in the sarcoplasmic reticulum of cardiac myocytes [45–48]. However, mutations in K + ion channel gene KCNJ2 have also been reported [49,50].…”

Unveiling Specific Triggers and Precipitating Factors for Fatal Cardiac Events in Inherited Arrhythmia Syndromes

“…31,32 RYR2 (encoding the cardiac ryanodine receptor), CAQS2 (encoding cardiac calsequestrin), KCNJ2 (encoding IK1: inwardly rectifying potassium currents), TRDN (encoding the junctional protein triadine) have been identified as causative genes for CPVT ( Table 1). 5,32,33 Recently, mutations in 2 (CALM1 and CALM2) of 3 genes (CALM1-3) encoding identical peptide sequences for the essential Ca 2+ -signaling protein calmodulin were reported to be associated with malignant forms of LQTS, CPVT and idiopathic VF. 34, 35 In CPVT, cytosolic Ca 2+ overload in ventricular myocytes or Purkinje cells generates inward currents thorough the Na + / Ca 2+ exchanger, leading to membrane depolarization called delayed afterdepolarization (DAD).…”