This study demonstrated that the pathogenic mechanism of a missense SYNE2 p.S4126R mutation-induced EDMD-5 condition involves disruption of the LINC complex interactions with nuclear envelope proteins including emerin and SUN2, ultimately leading to reduced expression of the nuclear membrane proteins and their delocalization from abnormally shaped nuclei of skeletal muscle cells, causing EDMD-related myopathy phenotypes. The gene discussed is EMD; the disease is Emery-Dreifuss muscular dystrophy.