The role of mutant protein level in autosomal recessive catecholamine dependent polymorphic ventricular tachycardia (CPVT2)

Guy Katz, Asher Shainberg, Edith Hochhauser, Efrat Kurtzwald-Josefson, Ahuva Issac, Dalia El-Ani, Dan Aravot, Arnon Afek, Jonathan G. Seidman, Christine E. Seidman, Michael Eldar, Michael Arad

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Humans and genetically engineered mice with recessively inherited CPVT develop arrhythmia which may arise due to malfunction or degradation of calsequestrin (CASQ2). We investigated the relation between protein level and arrhythmia severity in CASQ2D307H/D307H (D307H), compared to CASQ2Δ/Δ (KO) and wild type (WT) mice. CASQ2 expression and Ca2+ transients were recorded in cardiomyocytes from neonatal or adult mice. Arrhythmia was studied in vivo using heart rhythm telemetry at rest, exercise and after epinephrine injection. CASQ2 protein was absent in KO heart. Neonatal D307H and WT hearts expressed significantly less CASQ2 protein than the level found in the adult WT. Adult D307H expressed only 20% of CASQ2 protein found in WT. Spontaneous Ca2+ release was more prevalent in neonatal KO cardiomyocytes (89%) compared to 33-36% of either WT or D307H, respectively, p < 0.001. Adult cardiomyocytes from both mutant mice had more Ca 2+ abnormalities compared to control (KO: 82%, D307H 63%, WT 12%, p < 0.01). Calcium oscillations were most common in KO cardiomyocytes. We then treated mice with bortezomib to inhibit CASQ2D307H degradation. Bortezomib increased CASQ2 expression in D307H hearts by ∼50% (p < 0.05). Bortezomib-treated D307H mice had lower CPVT prevalence and less premature ventricular beats during peak exercise. No benefit against arrhythmia was observed in bortezomib treated KO mice. These results indicate that the mutant CASQ2D307H protein retains some of its physiological function. Its expression decreases with age and is inversely related to arrhythmia severity. Preventing the degradation of mutant protein should be explored as a possible therapeutic strategy in appropriate CPVT2 patients.

Original languageEnglish
Pages (from-to)1576-1583
Number of pages8
JournalBiochemical Pharmacology
Issue number11
StatePublished - 1 Dec 2013

Bibliographical note

Funding Information:
This work was funded by Israel Science Foundation grants 876/2005 and 763/10.


  • Arrhythmia
  • Bortezomib
  • Calcium transients
  • Calsequestrin
  • Mouse model
  • Protein degradation


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