Related Experiment Video
Updated: Jun 17, 2026
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
Sudden infant death syndrome in mice with an inherited mutation in RyR2
Nitin Mathur1, Subeena Sood, Sufen Wang
1Department of Molecular Physiology and Biophysics, Division of Cardiology, Baylor College of Medicine, Houston, TX 77030, USA.
Background:
Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice.
Methods And Results:
Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription-polymerase chain reaction and Western blotting showed that expression levels of other calcium handling proteins were unaltered, suggesting that calcium leak through mutant RyR2 underlies arrhythmogenesis and sudden death in young R176Q/+ mice.
Conclusions:
Our findings demonstrate that a gain-of-function mutation in RyR2 confers an increased risk of cardiac arrhythmias and sudden death in young mice and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with sudden infant death syndrome.
Insights
Mutations in the cardiac ryanodine receptor gene (RyR2) increase sudden death risk in young mice. This RyR2 mutation causes arrhythmias and calcium leaks, providing a model for sudden infant death syndrome research.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Mutations in the cardiac ryanodine receptor gene (RyR2) are linked to sudden infant death syndrome.
- Gain-of-function mutations may increase susceptibility to cardiac arrhythmias.
Purpose of the Study:
- To investigate if a gain-of-function RyR2 mutation (R176Q) increases cardiac arrhythmia and sudden death risk in young mice.
- To establish a mouse model for studying sudden infant death syndrome.
Main Methods:
- Prospective monitoring of sudden death incidence in R176Q/+ mice and wild-type littermates.
- Optical mapping of cardiac electrical activity and intracellular calcium.
- Surface ECGs and intracardiac pacing studies.
- Analysis of calcium handling protein expression.
Main Results:
- R176Q/+ mice exhibited higher sudden death rates compared to controls.
- Neonatal R176Q/+ mice showed increased ventricular ectopy and spontaneous calcium releases.
- R176Q/+ mice developed more arrhythmias upon provocation and had an arrhythmogenic substrate.
- Calcium leak through mutant RyR2, not altered protein expression, underlies arrhythmogenesis.
Conclusions:
- Gain-of-function RyR2 mutation increases cardiac arrhythmia and sudden death risk in young mice.
- Young R176Q/+ mice serve as a valuable model for sudden infant death syndrome research.
- This model aids in understanding genetic and environmental risk factors for SIDS.
