Novel truncating Desmin mutation Arg150Stop disrupts structural integrity and cellular homeostasis by formation of persistent aggregate-like structure.

Desminopathies are a heterogeneous group of myofibrillar myopathies defined by the presence of desmin-positive aggregates that compromise cytoskeletal integrity in skeletal and cardiac muscle. Although desmin knockout models and several truncating mutations typically result in a functional null phenotype without inclusion body formation, the molecular consequences of specific stop-gain variants remain poorly understood. In this study, we investigated the pathogenic mechanism of a novel Desmin (DES) nonsense mutation, NM_001927.4:c.448 C > T; p.(Arg150Stop), previously identified in an Indian patient with congenital myopathy. This premature stop codon lies within the Linker 1 A domain and is predicted to generate a truncated protein lacking the C-terminal tail. To delineate its functional consequences, we used two complementary experimental approaches: transient overexpression of the Arg150Stop mutant in skeletal and cardiac myocytes, and a CRISPR/Cas9-engineered homozygous Arg150stop cardiomyocyte line (Des