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Updated: Jun 20, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Ryanodine receptor (RyR2) mutations in sudden cardiac death: studies in extended pedigrees and phenotypic
Annukka Marjamaa1, Päivi Laitinen-Forsblom, Anetta Wronska
1Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland. annukka.marjamaa@helsinki.fi
Background:
Catecholaminergic polymorphic ventricular tachycardia caused by mutations in the RyR2 gene manifests as severe arrhythmias, and may provide a candidate for sudden cardiac deaths.
Methods:
We screened 19 victims of SCD for mutations in the RyR2 gene by direct sequencing, and analyzed DNAs from available family members and from 300 controls. Medico-legal investigations were conducted by experienced pathologists. We performed resting ECG, cardiac ultrasonography, exercise stress test, epinephrine test and 24-hour ambulatory ECG recording to related mutation carriers (n = 17). The single channel recordings of the mutant RyR2s were conducted in planar lipid bilayers, and the open probabilities were determined by sequential addition of CaCl(2) to the cis-side.
Results:
We identified two novel RyR2 missense mutations (G2145R and R3570W) in three victims of SCD. The surviving carriers of these mutations exhibited only minor, if any structural abnormalities, and two carriers of R3570W showed ventricular arrhythmias predominantly at rest. Single channel recordings revealed a gain-of-function defect in native unphosphorylated R3570W and a similar but milder defect in native G2145R.
Conclusions:
RyR2 mutations manifesting as a gain-of-function defect in vitro may be detectable in some cases of SCD. Not all RyR2 mutations lead to a uniform, highly penetrant CPVT phenotype.
Insights
Novel RyR2 gene mutations were found in victims of sudden cardiac death (SCD). These RyR2 mutations can cause gain-of-function defects, leading to arrhythmias, but not all mutations result in a severe CPVT phenotype.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Sudden Cardiac Death Etiology
Background:
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is linked to RyR2 gene mutations.
- CPVT can cause severe arrhythmias and sudden cardiac death (SCD).
Purpose of the Study:
- Investigate RyR2 gene mutations in victims of SCD.
- Determine the functional consequences of identified RyR2 mutations.
Main Methods:
- Screened 19 SCD victims for RyR2 mutations via direct sequencing.
- Conducted genetic analysis on family members and controls.
- Performed clinical evaluations and in vitro single channel recordings of RyR2 variants.
Main Results:
- Identified two novel RyR2 missense mutations (G2145R, R3570W) in three SCD victims.
- RyR2 mutation carriers showed minor abnormalities but some had ventricular arrhythmias.
- In vitro recordings revealed gain-of-function defects in the identified RyR2 mutations.
Conclusions:
- RyR2 mutations causing gain-of-function defects are potential contributors to SCD.
- The clinical presentation of RyR2 mutations can vary, not always leading to highly penetrant CPVT.
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