The E262K mutation in Lamin A links nuclear proteostasis imbalance to laminopathy-associated premature aging.
Aging Cell
; 21(11): e13688, 2022 11.
Article
em En
| MEDLINE
| ID: mdl-36225129
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 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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Senilidade Prematura
/
Laminopatias
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Adolescent
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Humans
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Male
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article