The Role of MYH6 Variants in atrial cardiomyopathy: insights from clinical observations and zebrafish models.

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.