The p.R249W Mutation in LMNA-Related Congenital Muscular Dystrophy Causes Nuclear Deformities and an Enrichment in Lamin A/C at the Ends of the Nucleus

LMNA-related congenital muscular dystrophy (L-CMD) is a rare genetic disorder that causes skeletal muscle weakening and wasting. Although L-CMD is caused by a variety of de novo point mutations in the LMNA gene, the p.R249W (Arg.249Trp.) pathogenic variant is the focus of this study because it is the most prevalent one among patients. We investigated the relationship between the p.R249W variant and the development of disease cellular phenotypes. We generated lentiviruses to separate p.R249W Lamin A/C localization from wild-type Lamin A/C localization, enabling us to examine how these proteins affect each other. We also developed an antibody specific for p.R249W Lamin A/C. Not only did we validate previous cellular phenotypes such as nuclear elongation, but we also identified a novel cellular phenotype. We observed overall Lamin A/C enrichment at the ends of nuclei in p.R249W patient cells. Our findings also suggest that wild-type Lamin A/C may recruit p.R249W Lamin A/C to the nuclear membrane, revealing molecular insights into the development of this dominant negative disease.