Abstract
A large genomic deletion in human cardiac ryanodine receptor (RYR2) gene has been detected in a number of unrelated families with various clinical phenotypes, including catecholaminergic polymorphic ventricular tachycardia (CPVT). This genomic deletion results in an in-frame deletion of exon-3 (Ex3-del). To understand the underlying disease mechanism of the RyR2 Ex3-del mutation, we generated a mouse model in which the RyR2 exon-3 sequence plus 15-bp intron sequences flanking exon-3 were deleted. Heterozygous Ex3-del mice (Ex3-del+/−) survived, but no homozygous Ex3-del mice were born. Unexpectedly, the Ex3-del+/− mice are not susceptible to CPVT. Ex3-del+/− cardiomyocytes exhibited similar amplitude but altered dynamics of depolarization-induced Ca2+ transients compared to wild type (WT) cells. Immunoblotting analysis revealed markedly reduced expression of RyR2 protein in the Ex3-del+/− mutant heart, indicating that Ex3-del has a major impact on RyR2 protein expression in mice. Cardiac specific, conditional knockout of the WT RyR2 allele in Ex3-del+/− mice led to bradycardia and death. Thus, the absence of CPVT and other phenotypes in Ex3-del+/− mice may be attributable to the predominant expression of the WT RyR2 allele as a result of the markedly reduced expression of the Ex3-del mutant allele. The effect of Ex3-del on RyR2 protein expression is discussed in relation to the phenotypic variability in individuals with the RyR2 exon-3 deletion.
Highlights
IntroductionThe cardiac Ca2+ release channel (ryanodine receptor type 2, RyR2) plays an essential role in excitation-contraction (EC) coupling and sarcoplasmic reticulum Ca2+ handling in the heart [1]
The cardiac Ca2+ release channel plays an essential role in excitation-contraction (EC) coupling and sarcoplasmic reticulum Ca2+ handling in the heart [1]
Of more than 150 disease-associated RyR2 mutations, exon-3 deletion (Ex3-del) is the only large genomic deletion found in the human RYR2 gene to date [2,11,12,13,14]
Summary
The cardiac Ca2+ release channel (ryanodine receptor type 2, RyR2) plays an essential role in excitation-contraction (EC) coupling and sarcoplasmic reticulum Ca2+ handling in the heart [1]. More than 150 mutations in RyR2 have been associated with different forms of cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), catecholaminergic idiopathic ventricular fibrillation, and atrial fibrillation [2,3,4,5]. A large genomic deletion (1.1–3.6 kb) in the RYR2 gene that covers exon-3 was identified in a number of unrelated families [11,12,13,14]. Individuals with this exon-3 deletion display a wide spectrum of clinical phenotypes, including CPVT, sinoatrial node dysfunction, bradycardia, atrial fibrillation, AV block, dilated cardiomyopathy, and left ventricular non-compaction
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