The E262K mutation in Lamin A links nuclear proteostasis imbalance to laminopathy-associated premature aging

Deleterious, mostly de novo, mutations in the lamin A (LMNA) gene cause spatio-functional nuclear abnormalities that result in several laminopathy-associated progeroid conditions. In this study, exome sequencing in a sixteen-year-old male with manifestations of premature aging led to the identification of a mutation, c.784G>A, in LMNA, resulting in a missense protein variant, p.Glu262Lys (E262K), that aggregates in nucleoplasm. While bioinformatic analyses reveal the instability and pathogenicity of LMNA(E262K), local unfolding of the mutation-harboring helical region drives the structural collapse of LMNA(E262K) into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNA(E262K), thereby reducing LMNA(E262K) degradation, aggregated LMNA(E262K) sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNA(E262K) disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure-function association of mutant LMNA(E262K) with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.