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The Role of MYH6 Variants in atrial cardiomyopathy: insights from clinical observations and zebrafish models
Yike Zhang1, Qing Wang2, Xiangao Ji1
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Insights
Genetic defects in MYH6 cause atrial cardiomyopathy, leading to impaired heart function and sarcomere disarray. This research highlights MYH6
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Atrial cardiomyopathy, often linked to genetic factors, is a potential precursor to atrial fibrillation.
- MYH6, encoding alpha-myosin heavy chain (α-MHC), is crucial for atrial sarcomere organization and contraction.
- Previous studies identified MYH6 variants in patients with familial atrial cardiomyopathy, but its precise role remains unclear.
Purpose of the Study:
- To investigate the role of MYH6 in atrial function and development.
- To elucidate the genetic causes of atrial cardiomyopathy.
- To understand the impact of MYH6 dysfunction on cardiac structure and gene expression.
Main Methods:
- Utilized CRISPR/Cas9 gene editing to create MYH6 knockout zebrafish.
- Assessed cardiac abnormalities through structural, electrical, and gene expression analyses.
- Performed transcriptomic sequencing to identify differentially expressed genes.
Main Results:
- MYH6 deficiency in zebrafish resulted in impaired atrial and ventricular function.
- Observed disordered sarcomere structure in the hearts of MYH6 knockout zebrafish.
- Transcriptomic analysis revealed significant gene expression changes in muscle development, calcium ion homeostasis, and sarcomere pathways.
Conclusions:
- MYH6 is essential for maintaining normal atrial function and cardiac development.
- MYH6 dysfunction contributes to atrial cardiomyopathy through sarcomeric abnormalities and atrial remodeling.
- These findings link sarcomeric defects to atrial remodeling and provide insights into atrial fibrillation pathogenesis.
Abstract:
Atrial cardiomyopathy, which often comes with underlying genetic defects, has been recognized as a possible substrate of atrial fibrillation. MYH6 encodes α-myosin heavy chain (α-MHC), predominantly expressed in the atria and pivotal in sarcomere organization and muscle contraction. Genetic investigation in patients with a family history of atrial cardiomyopathy identified three probands carrying MYH6 variants (D629N, V893M, A1327T). However, the role of MYH6 in atrial diseases has not been fully elucidated, and the genetic cause of atrial cardiomyopathy needs further investigation. Here, we employed CRISPR/Cas9 to generate myh6 knockout zebrafish, assessing cardiac abnormalities in structural, electrical, and gene expression levels through diverse methodologies. Our findings revealed that myh6 defects in zebrafish impaired atrial and ventricular function and disordered sarcomere, which underscores the pivotal role of MYH6 in maintaining atrial function and development. Transcriptomic sequencing also identified 1318 differentially expressed genes enriched in muscle development, calcium ion homeostasis, and sarcomere pathways. The association between MYH6 dysfunction and atrial cardiomyopathy highlights the role of sarcomeric abnormalities in atrial remodeling, a process implicated in atrial fibrillation.
