Impaired Dynamic Sarcoplasmic Reticulum Ca Buffering in Autosomal Dominant CPVT2.

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening arrhythmia triggered by stress.
• Mutations in the calsequestrin-2 gene (CASQ2) are a common cause of CPVT.
• The mechanism of autosomal dominant CPVT2 linked to CASQ2 variants like K180R remains unclear.

Purpose of the Study:

• To investigate the molecular mechanism underlying autosomal dominant CPVT2 caused by the CASQ2-K180R variant.
• To elucidate how CASQ2-K180R affects cardiac calcium handling and arrhythmogenesis.

Main Methods:

• Generation of a K180R mouse model using CRISPR/Cas9.
• In vivo ECG recordings and ex vivo cardiomyocyte studies.
• Analysis of SR calcium kinetics, protein levels, and Ca-handling proteins.

Main Results:

• K180R mice display an autosomal dominant CPVT phenotype under stress.
• K180R cardiomyocytes show increased spontaneous SR Ca release and delayed afterdepolarizations.
• The K180R variant impairs dynamic intra-SR Ca buffering without altering total SR Ca or Casq2 levels.

Conclusions:

• CASQ2-K180R causes CPVT2 through a novel mechanism distinct from recessive CASQ2 variants.
• Impaired dynamic SR Ca buffering by K180R leads to arrhythmias.
• This study provides crucial insights into the molecular basis of autosomal dominant CPVT2.