A Type 2 Ryanodine Receptor Variant in the Helical Domain 2 Associated with an Impairment of the Adrenergic Response

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered by exercise or acute emotion in patients with normal resting electrocardiogram. The major disease-causing gene is RYR2, encoding the cardiac ryanodine receptor (RyR2). We report a novel RYR2 variant, p.Asp3291Val, outside the four CPVT mutation hotspots, in three CPVT families with numerous sudden deaths. This missense variant was first identified in a four-generation family, where eight sudden cardiac deaths occurred before the age of 30 in the context of adrenergic stress. All affected subjects harbored at least one copy of the RYR2 variant. Three affected sisters were homozygous for the variant. The same variant was found in two additional CPVT families. It is located in the helical domain 2 and changes a negatively charged amino acid widely conserved through evolution. Functional analysis of D3291V channels revealed a normal response to cytosolic Ca2+, a markedly reduced luminal Ca2+ sensitivity and, more importantly, an absence of normal response to 8-bromo-cAMP and forskolin stimulation in both transfected HEK293 and HL-1 cells. Our data support that the D3291V-RyR2 is a loss-of-function RyR2 variant responsible for an atypical form of CPVT inducing a mild dysfunction in basal conditions but leading potentially to fatal events through its unresponsiveness to adrenergic stimulation.

The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease

“…The RyR2 mutation associated with idiopathic ventricular fibrillation confirmed as a loss-of-function mutation exhibiting Ca 2+ release deficiency ( 66 ). However, a recent study identified a loss-of-function mutation D3291V, which markedly reduced luminal Ca 2+ sensitivity, and blunted response to adrenergic stimulation, also exhibiting a CPVT phenotype ( 116 ). The relationship between gain-of-function or loss-of-function and the clinical phenotype still needs to be elucidated ( 117 ).…”