title: A type 2 ryanodine receptor variant associated with reduced Ca2+release and short-coupled torsades de pointes ventricular arrhythmia.
abstract: 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.
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujii
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murayama
authors.affiliation: Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
authors.affiliation: Department of Pediatric Cardiology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: INSERM, UMR U1166, ICAN, Paris, France; Sorbonne Universites, UPMC Univ Paris 06, UMR S1166, Paris, France.
authors.forename: Malorie
authors.initials: M
authors.lastname: Blancard
authors.affiliation: Department of Cardiovascular Medicine, Tenriyorozu Hospital, Nara, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Cardiovascular Medicine, Saiseikai Izumio Hospital, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiovascular Medicine, Saiseikai Izumio Hospital, Osaka, Japan.
authors.forename: Yumie
authors.initials: Y
authors.lastname: Matsui
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ichikawa
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sonoda
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Ohkubo
authors.affiliation: Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Watanabe
authors.affiliation: INSERM, UMR U1166, ICAN, Paris, France; Sorbonne Universites, UPMC Univ Paris 06, UMR S1166, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan. Electronic address: horie@belle.shiga-med.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000328:Adult; D015220:Calcium Channels / Q000378:metabolism*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018570:Risk Assessment; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D012494:Sampling Studies; D015996:Survival Rate; D017180:Tachycardia, Ventricular / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D016171:Torsades de Pointes / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Catecholaminergic polymorphic ventricular tachycardia; Idiopathic ventricular fibrillation; Long QT; RyR2; Torsades de pointes