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

SUBMITTER: Ghosh DK 

PROVIDER: S-EPMC9649601 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature