SYNE2 encodes nesprin-2, a multi-isomeric scaffolding protein that serves as a critical component of the LINC (Linker of Nucleoskeleton and Cytoskeleton) complex at the nuclear envelope 1. The protein maintains subcellular spatial organization by forming linking networks between organelles and the actin cytoskeleton 1. In cardiac muscle, specific SYNE2 isoforms localize to the Z-disc and I-band of the sarcomere, where they function as scaffold proteins interacting with telethonin and FHL-2, potentially regulating sarcomeric organization 2. Beyond nuclear envelope functions, SYNE2 plays crucial roles in nuclear positioning and migration through its association with motor protein complexes 1. Mutations in SYNE2 are associated with Emery-Dreifuss muscular dystrophy type 5 (EDMD5), characterized by progressive muscle weakness, contractures, and cardiac conduction defects 34. EDMD-associated SYNE2 mutations impair protein interactions with telethonin and FHL-2, suggesting disrupted sarcomeric function contributes to cardiomyopathy 2. Additionally, SYNE2 variants have been associated with hepatocellular carcinoma outcomes and p21 expression regulation 5. The protein's diverse subcellular localizations and molecular interactions underscore its importance in maintaining cellular architecture and its involvement in multiple disease pathways 1.