title: A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia.
abstract: Catecholaminergic 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.
  
  
  
  Several 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.
  
  
  
  A 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.
  
  
  
  This 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.
authors.affiliation: BC Inherited Arrhythmia Program, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roston
authors.affiliation: Libin Cardiovascular Institute of Alberta, Department of Physiology & Pharmacology and Department Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada.
authors.forename: Wenting
authors.initials: W
authors.lastname: Guo
authors.affiliation: BC Inherited Arrhythmia Program, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
authors.affiliation: Libin Cardiovascular Institute of Alberta, Department of Physiology & Pharmacology and Department Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada.
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
authors.affiliation: BC Inherited Arrhythmia Program, Vancouver, BC, Canada; Child and Family Research Institute, Vancouver, BC, Canada; Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.affiliation: Libin Cardiovascular Institute of Alberta, Department of Physiology & Pharmacology and Department Biochemistry & Molecular Biology, University of Calgary, Calgary, AB, Canada.
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
authors.affiliation: BC Inherited Arrhythmia Program, Vancouver, BC, Canada; Child and Family Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address: alehman@cw.bc.ca.
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006330:Heart Defects, Congenital / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D055815:Young Adult; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D005819:Genetic Markers; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Arrhythmia; Catecholaminergic polymorphic ventricular tachycardia; Left ventricular non-compaction; Ryanodine receptor-2; Sudden unexpected death