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A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical

Thomas M Roston1, Wenting Guo2, Andrew D Krahn3

  • 1BC 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.

Journal of Electrocardiology
|September 21, 2016
PubMed
Abstract

Insights

A novel RYR2 mutation (I4855M) causes a rare overlap syndrome of catecholaminergic polymorphic ventricular tachycardia (CPVT) and left ventricular non-compaction (LVNC). This loss-of-function mutation has a dominant-negative effect on RyR2, potentially leading to sudden death.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy often caused by RYR2 mutations.
  • Left ventricular non-compaction (LVNC) is a genetic cardiomyopathy.
  • A rare overlap syndrome of LVNC and CPVT has been linked to RYR2 exon 3 deletion.

Purpose of the Study:

  • To characterize the phenotypic spectrum and molecular basis of a novel RYR2 mutation in a family with LVNC and CPVT.
  • To investigate the structural and functional impact of the identified RYR2 mutation.

Main Methods:

  • Clinical and genetic assessments of an affected family.
  • Homology modeling of the RYR2 pore-region to predict mutation impact.
  • In vitro Ca2+-release assays using HEK293 cells expressing the RYR2 mutant.

Main Results:

  • A multigenerational family presented with sudden death, atypical CPVT, and LVNC.
  • Genetic testing identified a novel RYR2 mutation (I4855M) in affected individuals.
  • In silico and functional studies indicated I4855M is a damaging loss-of-function mutation with a dominant-negative effect on wild-type RYR2.

Conclusions:

  • A novel RYR2 variant (I4855M) is associated with a potentially lethal overlap syndrome of LVNC and atypical CPVT.
  • The mutation acts as a loss-of-function, exerting a dominant-negative effect on RYR2.
  • This finding expands the understanding of RYR2-related cardiomyopathies and arrhythmias.
Keywords:
ArrhythmiaCatecholaminergic polymorphic ventricular tachycardiaLeft ventricular non-compactionRyanodine receptor-2Sudden unexpected death

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