title: S4153R is a gain-of-function mutation in the cardiac Ca(2+) release channel ryanodine receptor associated with catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation.
abstract: Mutations in ryanodine receptor 2 (RYR2) gene can cause catecholaminergic polymorphic ventricular tachycardia (CPVT). The novel RYR2-S4153R mutation has been implicated as a cause of CPVT and atrial fibrillation. The mutation has been functionally characterized via store-overload-induced Ca(2+) release (SOICR) and tritium-labelled ryanodine ([(3)H]ryanodine) binding assays. The S4153R mutation enhanced propensity for spontaneous Ca(2+) release and reduced SOICR threshold but did not alter Ca(2+) activation of [(3)H]ryanodine binding, a common feature of other CPVT gain-of-function RYR2 mutations. We conclude that the S4153R mutation is a gain-of-function RYR2 mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation.
authors.affiliation: Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Pavel
authors.initials: P
authors.lastname: Zhabyeyev
authors.forename: Florian
authors.initials: F
authors.lastname: Hiess
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Wang
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Liu
authors.forename: S R
authors.initials: SR
authors.lastname: Wayne Chen
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D001281:Atrial Fibrillation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel