Catecholamine-induced polymorphic ventricular tachycardia (CPVT) is a familial 
disorder caused by cardiac ryanodine receptor type 2 (RyR2) or calsequestrin 2 
(CASQ2) gene mutations. To define how CASQ2 mutations cause CPVT, we produced 
and studied mice carrying a human D307H missense mutation (CASQ(307/307)) or a 
CASQ2-null mutation (CASQ(DeltaE9/DeltaE9)). Both CASQ2 mutations caused 
identical consequences. Young mutant mice had structurally normal hearts but 
stress-induced ventricular arrhythmias; aging produced cardiac hypertrophy and 
reduced contractile function. Mutant myocytes had reduced CASQ2 and increased 
calreticulin and RyR2 (with normal phosphorylated proportions) but unchanged 
calstabin levels, as well as reduced total sarcoplasmic reticulum (SR) Ca(2+), 
prolonged Ca(2+) release, and delayed Ca(2+) reuptake. Stress further diminished 
Ca(2+) transients, elevated cytosolic Ca(2+), and triggered frequent, 
spontaneous SR Ca(2+) release. Treatment with Mg(2+), a RyR2 inhibitor, 
normalized myocyte Ca(2+) cycling and decreased CPVT in mutant mice, indicating 
RyR2 dysfunction was critical to mutant CASQ2 pathophysiology. We conclude that 
CPVT-causing CASQ2 missense mutations function as null alleles. In the absence 
of CASQ2, calreticulin, a fetal Ca(2+)-binding protein normally downregulated at 
birth, remains a prominent SR component. Adaptive changes to CASQ2 deficiency 
(increased posttranscriptional expression of calreticulin and RyR2) maintained 
electrical-mechanical coupling, but increased RyR2 leakiness, a paradoxical 
response further exacerbated by stress. The central role of RyR2 dysfunction in 
CASQ2 deficiency unifies the pathophysiologic mechanism underlying CPVT due to 
RyR2 or CASQ2 mutations and suggests a therapeutic approach for these inherited 
cardiac arrhythmias.