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Heart Rhythm. 2017 Jan;14(1):98-107. doi: 10.1016/j.hrthm.2016.10.015. Epub 2016 Oct 15.

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

Author information

1
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
2
Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
3
Department of Pediatric Cardiology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
4
INSERM, UMR U1166, ICAN, Paris, France; Sorbonne Universites, UPMC Univ Paris 06, UMR S1166, Paris, France.
5
Department of Cardiovascular Medicine, Tenriyorozu Hospital, Nara, Japan.
6
Department of Cardiovascular Medicine, Saiseikai Izumio Hospital, Osaka, Japan.
7
Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
8
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. Electronic address: horie@belle.shiga-med.ac.jp.

Abstract

BACKGROUND:

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).

OBJECTIVE:

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

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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

KEYWORDS:

Catecholaminergic polymorphic ventricular tachycardia; Idiopathic ventricular fibrillation; Long QT; RyR2; Torsades de pointes

PMID:
27756708
DOI:
10.1016/j.hrthm.2016.10.015
[Indexed for MEDLINE]
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