ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle. Located in the sarcomere Z-disk, it functions as a link between anti-parallel actin filaments and binds N-terminal titins, contributing to sarcomere stability [1].

Genetic variants in ACTN2 are associated with several forms of (cardio)myopathy [2]. Suppression of Actn2 in H9c2 cells under dexamethasone treatment impairs calcium uptake, increases hypertrophy, and elevates hypertrophic molecular biomarkers, with excessive activation of the MAPK pathway and ERK cascade [3]. A recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy with asymmetric, progressive muscle weakness in the lower extremities [4]. Dominant ACTN2 mutations can cause a skeletal muscle disorder named "Multiple structured Core Disease" (MsCD), and zebrafish and mouse models expressing mutated alpha-actinin-2 recapitulate the abnormal muscle function and structure seen in patients [5].

In conclusion, ACTN2 is essential for cardiac and skeletal muscle sarcomeric function. Studies using cell models and animal models like zebrafish and mice have revealed its role in various myopathies, including cardiomyopathies and skeletal muscle disorders, highlighting its importance in understanding the mechanisms of these diseases.