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.