Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia

Abstract

Background-Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of Ϸ30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). Methods and Results-In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. Conclusions-Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling. Key Words: ryanodine receptor calcium release channel Ⅲ sarcoplastic reticulum Ⅲ tachycardia Ⅲ genetics I nherited cardiac disorders associated with a propensity to malignant ventricular tachyarrhythmias constitute an important cause of sudden death in both young and adult individuals. 1 The identification of defective genes that cause the clinical phenotype has the potential to allow molecular diagnostics to identify benign arrhythmias from those that should be treated. In addition, knowledge of the defective protein and its cellular function will allow the development of targeted therapies. Defective genes that cause several of these types of arrhythmic disorders have been identified to date and, thus far, they primarily code for various ion channels in the cardiomyocyte plasma membrane.Long-QT syndrome, which is characterized by a delayed repolarization phase of the cardiac action potential and a risk of life-threatening tachyarrhythmias such as torsade de pointes, was recently shown to be caused by inactivating mutations of the cardiac potassium channels KCNQ1, HERG, minK, or MiRP or activating mutations of the sodium channel SCN5A. 2,3 Activating mutations of SCN5A may cause Brugada's syndrome, a rare dominantly inherited electrophysiological disorder with right bundle branch block on ECG and a propensity to ventricular fibrillation. 4 Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by fatty infiltration and fibrosis of the myocardium, resulting in electric instability and risk of fatal ventricular arrhythmias. At least 6 chromosomal loci for the autosomal-dominant form of ARVD have been mapped, 5-10 and a deletion of the p...

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

“…These findings therefore are in accord with the clinical observation that patients with mutated RyRs display a catecholaminergic polymorphic ventricular tachycardia and therefore show arrhythmias only during adrenergic stimulation. 11,12 Our results show that an acute increase of RyR opening can cause diastolic Ca 2ϩ release until SR Ca 2ϩ decreases. It is therefore possible that clinically an acute sensitization of the RyR would be arrhythmogenic.…”

“…8 This is thought to be responsible for the arrhythmogenic diastolic Ca 2ϩ release in conditions such as digitalis intoxication 6,7,9 and reperfusion following ischemia; 10 and (2) changes in the properties of the RyR. Mutations in the human RyR [11][12][13] or accessory proteins such as calsequestrin 14 increase susceptibility to lethal arrhythmias such as catecholaminergic polymorphic ventricular tachycardia. It has also been suggested that in heart failure, the open probability (P o ) of the normal RyR may be increased by protein kinase A-dependent phosphorylation and that this may be arrhythmogenic.…”

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

“…Further, alterations in calcium signaling through ryanodine receptor mutations have been shown to cause sudden cardiac death and catecholaminergic polymorphic ventricular tachycardia. Therefore, calcium signaling irregularities might be a component of the frequent sudden cardiac death seen in HCM [2,[43][44][45][46][47].…”

Energetic and Structural Analysis of the Role of Tryptophan 59 in FKBP12

“…The results of Shou et al, (1998) are consistent with the finding that paediatric organ transplant patients given high doses of FK506 developed hypertrophic cardiomyopathy associated with clinically severe heart failure (Atkinson, 1995). Further, genetically transmitted mutations in the hRyR2 gene causes stress-induced bidirectional ventricular tachycardia (Laitinen et al, 2001;Priori et al, 2001), leading to cardiac arrest and sudden death. It has been suggested that these mutations disrupt the FKBP12.6 association, leaving RyR2 in an open state (Marks, 2002).…”