Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Alpha-actinin 2 (ACTN2) is crucial for anchoring actin in cardiac sarcomeres.
• The precise mechanisms linking ACTN2 mutations to myocardial disease remain unclear.
• This study investigates novel ACTN2 mutations to elucidate ACTN2's physiological role in the heart.

Purpose of the Study:

• To characterize patients with novel ACTN2 mutations.
• To understand the functional consequences of ACTN2 mutations on cardiac cells.
• To reveal the molecular mechanisms underlying ACTN2-associated myocardial disease.

Main Methods:

• Identified ACTN2 protein-truncating variants in patients.
• Utilized patient-derived iPSC-cardiomyocytes for analysis.
• Employed RNA sequencing, video-based edge detection, immunohistochemistry, electron microscopy, co-immunoprecipitation, mass-spectrometry, and confocal microscopy.

Main Results:

• Patient iPSC-cardiomyocytes exhibited hypertrophy, sarcomeric disarray, impaired contractility, and aberrant calcium signaling.
• Truncated ACTN2 incorporated into sarcomeres, causing Z-disc ultrastructure abnormalities.
• Mass-spectrometry identified an ACTN2 interactome, revealing disrupted interactions with ACTN1 and GJA1, potentially causing arrhythmias and relaxation defects.

Conclusions:

• ACTN2 truncation is causally linked to myocardial disease through recessive inheritance.
• These findings enhance understanding of ACTN2's role in human cardiac function.
• Disruption of ACTN2 interactions contributes to cardiac dysfunction and disease phenotypes.