Department of Medical Genetics, Manipal Academy of Higher Education, Kasturba Medical College, Manipal, Manipal, India.
Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, India.
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 LMNA , local unfolding of the mutation-harboring helical region drives the structural collapse of LMNA into aggregates. The E262K mutation also disrupts SUMOylation of lysine residues by preventing UBE2I binding to LMNA , thereby reducing LMNA degradation, aggregated LMNA sequesters nuclear chaperones, proteasomal proteins, and DNA repair proteins. Consequently, aggregates of LMNA disrupt nuclear proteostasis and DNA repair response. Thus, we report a structure-function association of mutant LMNA with toxicity, which is consistent with the concept that loss of nuclear proteostasis causes early aging in laminopathies.
在核纤层蛋白 A（LMNA）基因中存在大量的新生致病变异，这些突变导致核的空间功能异常，进而引起几种与核纤层蛋白病相关的早老症候群。在这项研究中，对一名表现出早衰症状的 16 岁男性进行外显子组测序，发现了 LMNA 基因中的一个突变 c.784G>A，导致了一个错义蛋白变异 p.Glu262Lys（E262K），该变异蛋白在核质中聚集。虽然生物信息学分析显示 LMNA 不稳定且具有致病性，但突变所在的螺旋区域局部展开会导致 LMNA 结构崩溃并形成聚集体。E262K 突变还通过阻止 UBE2I 与 LMNA 结合，从而阻止赖氨酸残基的 SUMO 化，进而减少 LMNA 的降解，导致聚集的 LMNA 会隔离核伴侣蛋白、蛋白酶体蛋白和 DNA 修复蛋白。因此，LMNA 的聚集体破坏了核内蛋白质稳态和 DNA 修复反应。因此，我们报告了突变型 LMNA 与毒性的结构-功能关联，这与核内蛋白质稳态丧失导致核纤层蛋白病早老的概念一致。
