Calsequestrin 2 (CASQ2) mutations increase expression of calreticulin and ryanodine receptors, causing catecholaminergic polymorphic ventricular tachycardia
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Key result
CASQ2 mutations in mice resulted in a 100% incidence of stress-induced ventricular arrhythmias compared to 0% in wild-type mice, driven by compensatory increases in calreticulin and ryanodine receptors.
Population
Mice carrying a human D307H missense mutation or a CASQ2-null mutation and wild-type controls.
Comparison
Genetic mutation of CASQ2 and subsequent stress… vs Wild-type (WT) mice and untreated mutant mice.
Design
Preclinical
Follow-up
Up to 35 weeks of age
Authors
Discussion
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Implication
CASQ2 mutations may trigger stress arrhythmias via RyR2 compensation in mice; leaves open translation to human CPVT therapy.
Key Points
- To elucidate the cellular and molecular mechanisms by which CASQ2 missense and null mutations trigger catecholaminergic polymorphic ventricular tachycardia.
- Generated and evaluated knock-in mice harboring either a human D307H missense mutation (CASQ2(307/307)) or a CASQ2-null mutation (CASQ2(DeltaE9/DeltaE9)).
- Assessed cardiac structure, contractile performance, stress-induced ventricular arrhythmias, and cardiomyocyte sarcoplasmic reticulum (SR) Ca2+ dynamics in young and aging mice.
- Administered the RyR2 inhibitor Mg2+ to evaluate its capacity to normalize myocyte Ca2+ handling and suppress arrhythmia induction.
- Both CASQ2 missense and null mutations functioned identically as null alleles, causing normal cardiac anatomy in youth but leading to stress-induced CPVT, progressive hypertrophy, and impaired contractility with age.
- Mutant myocytes exhibited absent CASQ2 alongside compensatory increases in calreticulin and RyR2, resulting in lower SR Ca2+ stores, prolonged Ca2+ transients, delayed reuptake, and spontaneous Ca2+ leak under stress.
- Treatment with Mg2+ normalized SR Ca2+ cycling and significantly attenuated CPVT in mutant mice, confirming uninhibited RyR2 leak as the core driver of CASQ2 pathogenesis.
Structured PICO
P
Population
Genetically engineered mice carrying human D307H missense or CASQ2-null mutations, evaluated at 14 to 35 weeks of age to study the pathophysiology of catecholaminergic polymorphic ventricular tachycardia.
E
Exposure
Genetic mutation of CASQ2 (D307H missense or exon 9 deletion) and subsequent stress testing (exercise or catecholamines) with or without Mg2+ (RyR2 inhibitor) treatment.
C
Comparator
Wild-type (WT) mice and untreated mutant mice.
O
Outcome
Development of catecholaminergic polymorphic ventricular tachycardia (CPVT), myocyte Ca2+ cycling, and expression levels of SR proteins (calreticulin, RyR2).surrogate
Main Result
Absolute Event Rate: 100% vs 0%
p-value: p=0.00001
CASQ2 missense mutations function as null alleles, leading to compensatory increases in calreticulin and RyR2 that maintain baseline function but cause CPVT under stress, which can be mitigated by RyR2 inhibition with Mg2+.
Limitations
- Animal model may not perfectly replicate human disease
- Late-onset hypertrophic remodeling mechanism remains uncertain in humans due to early lethality of CASQ2 mutations
Cite This Study
Alcalai et al. (2007) studied Catecholaminergic polymorphic ventricular tachycardia. CASQ2 mutations (D307H or exon 9 deletion) vs. Wild-type mice was evaluated on Incidence of exercise-induced ventricular premature beats or nonsustained ventricular tachycardia (p=0.00001). CASQ2 mutations in mice resulted in a 100% incidence of stress-induced ventricular arrhythmias compared to 0% in wild-type mice, driven by compensatory increases in calreticulin and ryanodine receptors.
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