Unexpected Structural and Functional Consequences of the R33Q Homozygous Mutation in Cardiac Calsequestrin

A Complex Arrhythmogenic Cascade in a Knock in Mouse Model

Nicoletta Rizzi, Nian Liu, Carlo Napolitano, Alessandra Nori, Federica Turcato, Barbara Colombi, Silvio Bicciato, Diego Arcelli, Alessandro Spedito, Mario Scelsi, Laura Villani, Giovanni Esposito, Simona Boncompagni, Feliciano Protasi, Pompeo Volpe, Silvia G. Priori

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by life threatening arrhythmias elicited by physical and emotional stress in young individuals. The recessive form of CPVT is associated with mutation in the cardiac calsequestrin gene (CASQ2). We engineered and characterized a homozygous CASQ2 mouse model that closely mimics the clinical phenotype of CPVT patients. CASQ2 mice develop bidirectional VT on exposure to environmental stress whereas CASQ2 myocytes show reduction of the sarcoplasmic reticulum (SR) calcium content, adrenergically mediated delayed (DADs) and early (EADs) afterdepolarizations leading to triggered activity. Furthermore triadin, junctin, and CASQ2-R33Q proteins are significantly decreased in knock-in mice despite normal levels of mRNA, whereas the ryanodine receptor (RyR2), calreticulin, phospholamban, and SERCA2a-ATPase are not changed. Trypsin digestion studies show increased susceptibility to proteolysis of mutant CASQ2. Despite normal histology, CASQ2 hearts display ultrastructural changes such as disarray of junctional electron-dense material, referable to CASQ2 polymers, dilatation of junctional SR, yet normal total SR volume. Based on the foregoings, we propose that the phenotype of the CASQ2 CPVT mouse model is portrayed by an unexpected set of abnormalities including (1) reduced CASQ2 content, possibly attributable to increased degradation of CASQ2-R33Q, (2) reduction of SR calcium content, (3) dilatation of junctional SR, and (4) impaired clustering of mutant CASQ2.

Original languageEnglish
Pages (from-to)298-306
Number of pages9
JournalCirculation Research
Volume103
Issue number3
DOIs
Publication statusPublished - Aug 1 2008

Fingerprint

Calsequestrin
Sarcoplasmic Reticulum
Mutation
Ryanodine Receptor Calcium Release Channel
Dilatation
Calreticulin
Calcium
Phenotype
Environmental Exposure
Psychological Stress
Trypsin
Muscle Cells
Proteolysis
Cluster Analysis
Adenosine Triphosphatases
Cardiac Arrhythmias
Digestion
Histology
Polymers
Electrons

Keywords

  • Calsequestrin
  • Genetics
  • Sudden death
  • Transgenic mice
  • Triggered activity

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Unexpected Structural and Functional Consequences of the R33Q Homozygous Mutation in Cardiac Calsequestrin : A Complex Arrhythmogenic Cascade in a Knock in Mouse Model. / Rizzi, Nicoletta; Liu, Nian; Napolitano, Carlo; Nori, Alessandra; Turcato, Federica; Colombi, Barbara; Bicciato, Silvio; Arcelli, Diego; Spedito, Alessandro; Scelsi, Mario; Villani, Laura; Esposito, Giovanni; Boncompagni, Simona; Protasi, Feliciano; Volpe, Pompeo; Priori, Silvia G.

In: Circulation Research, Vol. 103, No. 3, 01.08.2008, p. 298-306.

Research output: Contribution to journalArticle

Rizzi, Nicoletta ; Liu, Nian ; Napolitano, Carlo ; Nori, Alessandra ; Turcato, Federica ; Colombi, Barbara ; Bicciato, Silvio ; Arcelli, Diego ; Spedito, Alessandro ; Scelsi, Mario ; Villani, Laura ; Esposito, Giovanni ; Boncompagni, Simona ; Protasi, Feliciano ; Volpe, Pompeo ; Priori, Silvia G. / Unexpected Structural and Functional Consequences of the R33Q Homozygous Mutation in Cardiac Calsequestrin : A Complex Arrhythmogenic Cascade in a Knock in Mouse Model. In: Circulation Research. 2008 ; Vol. 103, No. 3. pp. 298-306.
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AU - Liu, Nian

AU - Napolitano, Carlo

AU - Nori, Alessandra

AU - Turcato, Federica

AU - Colombi, Barbara

AU - Bicciato, Silvio

AU - Arcelli, Diego

AU - Spedito, Alessandro

AU - Scelsi, Mario

AU - Villani, Laura

AU - Esposito, Giovanni

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