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

Aging Cell. 2022 Nov;21(11):e13688. doi: 10.1111/acel.13688. Epub 2022 Oct 12.


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 LMNAE262K , local unfolding of the mutation-harboring helical region drives the structural collapse of LMNAE262K into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNAE262K , thereby reducing LMNAE262K degradation, aggregated LMNAE262K sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNAE262K disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure-function association of mutant LMNAE262K with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.

Keywords: lamin A; laminopathy-associated progeroid disorder; loss of DNA damage repair; nuclear proteostasis imbalance; protein aggregation; protein instability.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Aging, Premature* / genetics
  • Humans
  • Lamin Type A / genetics
  • Laminopathies*
  • Male
  • Mutation / genetics
  • Proteostasis / genetics


  • Lamin Type A