A type 2 ryanodine receptor variant associated with reduced Ca²⁺ release and short-coupled torsades de pointes...

Ventricular fibrillation may be caused by premature ventricular contractions (PVCs) whose coupling intervals are <300 ms, a characteristic of the short-coupled variant of torsades de pointes (scTdP).

The purpose of this study was to analyze the underlying cardiac ryanodine receptor (RyR2) variants in patients with scTdP.

Seven patients with scTdP (mean age 34 ± 12 years; 4 men and 3 women) were enrolled in this study. The RyR2 gene was screened by targeted gene sequencing methods; variant minor allele frequency was confirmed in 3 databases; and the pathogenicity was investigated in silico analysis using multiple tools. The activity of wild-type and mutant RyR2 channels was evaluated by monitoring Ca²⁺ signals of HEK293 cells with a [³H]ryanodine binding assay.

The mean coupling interval of PVCs was 282 ± 13 ms. The 12-lead electrocardiogram had no specific findings except PVCs with an extremely short-coupling interval. Genetic analysis revealed 3 novel RyR2 variants and 1 polymorphism, all located in the cytoplasmic region. p.Ser4938Phe was not detected in 3 databases, and in silico analysis indicated its pathogenicity. In functional analysis, p.Ser4938Phe demonstrated loss of function and impaired RyR2 channel Ca²⁺ release, while 2 other variants, p.Val1024Ile and p.Ala2673Val, had mild gain-of-function effects but were similar to the polymorphism p.Asn1551Ser.

We identified an RyR2 variant associated with reduced Ca²⁺ release and short-coupled torsades de pointes ventricular arrhythmia. The mechanisms of arrhythmogenesis remain unclear.