Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia
Björn C. Knollmann, … , Clara Franzini-Armstrong, Karl Pfeifer
Björn C. Knollmann, … , Clara Franzini-Armstrong, Karl Pfeifer
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2510-2520. https://doi.org/10.1172/JCI29128.
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Research Article Cardiology

Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia

Abstract

Cardiac calsequestrin (Casq2) is thought to be the key sarcoplasmic reticulum (SR) Ca2+ storage protein essential for SR Ca2+ release in mammalian heart. Human CASQ2 mutations are associated with catecholaminergic ventricular tachycardia. However, homozygous mutation carriers presumably lacking functional Casq2 display surprisingly normal cardiac contractility. Here we show that Casq2-null mice are viable and display normal SR Ca2+ release and contractile function under basal conditions. The mice exhibited striking increases in SR volume and near absence of the Casq2-binding proteins triadin-1 and junctin; upregulation of other Ca2+-binding proteins was not apparent. Exposure to catecholamines in Casq2-null myocytes caused increased diastolic SR Ca2+ leak, resulting in premature spontaneous SR Ca2+ releases and triggered beats. In vivo, Casq2-null mice phenocopied the human arrhythmias. Thus, while the unique molecular and anatomic adaptive response to Casq2 deletion maintains functional SR Ca2+ storage, lack of Casq2 also causes increased diastolic SR Ca2+ leak, rendering Casq2-null mice susceptible to catecholaminergic ventricular arrhythmias.

Authors

Björn C. Knollmann, Nagesh Chopra, Thinn Hlaing, Brandy Akin, Tao Yang, Kristen Ettensohn, Barbara E.C. Knollmann, Kenneth D. Horton, Neil J. Weissman, Izabela Holinstat, Wei Zhang, Dan M. Roden, Larry R. Jones, Clara Franzini-Armstrong, Karl Pfeifer

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Figure 1

Generating the Casq2– allele.

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Generating the Casq2– allele. ...
(A) The Casq2 exon 1 sequence as determined by 5′ RACE. Four transcriptional starts were identified and are marked with filled arrowheads. Nucleotide number 1 represents the 5′ end of the longest identified transcript. Exon 1 includes 3 in-frame ATG translational starts (underlined). Only the second ATG is conserved in other vertebrates, and only this ATG is predicted to encode a leader sequence that would appropriately target the nascent CASQ2 peptide to the SR. (B) Wild-type (i) and mutant (ii) alleles of the Casq2 locus are depicted. The Casq2 locus spans more than 60 kb and includes 11 exons (vertical bars). Exon 1 encodes the ATG initiation codon and the first 78 amino acids. The Casq2– allele is a 1.1-kb deletion that removes 561 bp of upstream sequences, including the presumptive Casq2 promoter (open oval) as well as the entire 431-bp exon 1 and 107 bp of intron 1.