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

Abstract

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.