MYBPC3 (c.194 C > T) mutation-mediated RyR2 dysfunction contributes to pathogenic phenotypes of DCM revealed by HiPSC...

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Genetics

Background:

• Dilated cardiomyopathy (DCM) is a major cause of heart failure and a primary reason for heart transplantation.
• The genetic basis and treatment options for DCM remain poorly understood, creating a significant patient burden.

Purpose of the Study:

• To investigate the pathogenic role of a novel MYBPC3 mutation in DCM.
• To establish and characterize a patient-specific induced pluripotent stem cell (hiPSC) model for DCM research.
• To explore potential therapeutic strategies targeting calcium dysregulation in DCM.

Main Methods:

• Identified a novel MYBPC3 mutation (c.194C>T) in a DCM patient.
• Generated patient-specific human induced pluripotent stem cells (hiPSCs) and derived cardiomyocytes (hiPSC-CMs).
• Utilized RNA sequencing and calcium imaging to analyze hiPSC-CMs and tested RyR2 inhibition.

Main Results:

• Patient-derived hiPSC-CMs displayed DCM characteristics: enlarged cells, abnormal sarcomeric structure, and calcium handling defects.
• RNA sequencing showed increased CASQ2 expression, impacting calsequestrin levels.
• Treatment with a RyR2 inhibitor (ryanodine) corrected aberrant calcium transients in DCM hiPSC-CMs.

Conclusions:

• The identified MYBPC3 mutation is a causative factor in DCM.
• Modulating RyR2 offers a potential therapeutic approach for DCM with calcium dysregulation.
• This study provides insights into DCM pathogenesis and a model for future research.