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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.

SUBMITTER: Ghosh DK

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

REPOSITORIES: biostudies-literature

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

Ghosh Debasish Kumar DK Pande Shruti S Kumar Jeevan J Yesodharan Dhanya D Nampoothiri Sheela S Radhakrishnan Periyasamy P Reddy Chilakala Gangi CG Ranjan Akash A Girisha Katta M KM

Aging cell 20221012 11

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 pathogenicit ...[more]

PMID: 36225129

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Project description:Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.

Dataset Information

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

Publications

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

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