CNR - Institute of Neuroscience CNR
Institute of Neuroscience


Molecular pathogenesis of ventricular arrhythmias

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a genetically transmitted disease characterized by stress- or emotion-induced life-threatening arrhythmias occurring in the structurally intact heart.

Mutations in the cardiac ryanodine receptor (RyR2) gene cause the autosomal dominant form. Mutations in the cardiac calsequestrin (CASQ2) gene are responsible for the rare autosomal recessive form of the disease.

Goal of our work is to unravel the molecular pathogenesis of CPVT caused by mutations of the CASQ2 gene. We identified two novel mutations in CASQ2 gene:R33Q, which was found in a CPVT patient with history of syncope and a brother who died suddenly at young age; L167H which was identified in a patient who also carried the deletion G112+5X, thus being the first patient with compound heterozygous CASQ2 mutations.

Based on our studies, we suggest that the PATHOLOGICAL MOLECULAR MECHANISM proceeds through:


In summary, each CASQ2 mutation, through single or combined molecular mechanisms, leads to a common final pathway to induce irregular, diastolic Ca transients and delayed after-depolarization (DADs) at the myocyte level.


Future studies: molecular pathogenesis of such phenotypes to pinpoint crucial steps for therapeutic interventions.
Specific aims in the model of recessive CPVT, the homozygous CASQ2R33Q/R33Q mouse:

  • post-natal expression pattern of CASQ2 and other sarcoplasmic reticulum proteins
  • mechanisms of down−regulation of CASQ2R33Q/R33Q protein
  • Ca transients and Ca sparks in isolated cardiomyocytes


  • Rizzi N, Liu N, Napolitano C, Nori A, Turcato F, Colombi B, Bicciato S, Arcelli D, Spedito A, Scelsi M, Villani L, Esposito G, Boncompagni S, Protasi F, Volpe P, Priori SG (2008) Unexpected structural and functional consequences of the R33Q homozygous mutation in cardiac calsequestrin: a complex arrhythmogenic cascade in a knock in mouse model. Circ. Res. 103:298-306.
  • Valle G, Galla D, Nori A, Priori SG, Gyorke S, de Filippis V, Volpe P (2008) Catecholaminergic polymorphic ventricular tachycardia-related mutations R33Q and L167H alter calcium sensitivity of human cardiac calsequestrin. Biochem. J. 413:291-303.
  • Qin J, Valle G, Nani A, Nori A, Rizzi N, Priori SG, Volpe P, Fill M (2008) Luminal Ca2+ regulation of single cardiac ryanodine receptors: insights provided by calsequestrin and its mutants. J. Gen. Physiol. 131:325-34.


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Pompeo Volpe

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