A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia

Abstract

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy usually caused by gain-of-function mutations ryanodine receptor type-2 (RyR2). Left ventricular non-compaction (LVNC) is an often genetic cardiomyopathy. A rare LVNC-CPVT overlap syndrome may be caused by exon 3 deletion in RyR2. We sought to characterize the phenotypic spectrum and molecular basis of a novel RyR2 mutation identified in a family with both conditions. MethodsSeveral members of an affected family underwent clinical and genetic assessments. A homology model of the RyR2 pore-region was generated to predict the location and potential impact of their RyR2 mutation. Ca2+-release assays were performed to characterize the functional impact of the RyR2 mutant expressed in HEK293 cells. ResultsA multigenerational family presented with a history of sudden death and a phenotype of atypical CPVT and LVNC. Genetic testing revealed a RYR2 mutation (I4855M) in two affected individuals. A homology model of the RyR2 pore-region showed that the I4855M mutant reside is located in the highly conserved ‘inner vestibule’, a water-filled cavity. I4855M may interfere with Ca2+ permeation and affect interactions between RyR2 pore subunits, and is thus predicted in silico to be damaging. Expression and functional studies in HEK293 cells revealed that I4855M inhibited caffeine-induced Ca2+ release and exerted a dominant-negative impact on wild type RyR2. ConclusionsThis study identifies a potentially lethal overlapping syndrome of LVNC and atypical CPVT related to a novel RYR2 variant. Structural and functional studies suggest that this is a loss-of-function mutation, which exerts a dominant-negative effect on wild type RyR2.