Studies of laminopathy-based progeria offer insights into aging-associated diseases and highlight the role of LMNA in chromatin organization. Mandibuloacral dysplasia type A (MAD) is a largely unexplored form of atypical progeria that lacks lamin A post-translational processing defects. Using iPSCs derived from a male MAD patient carrying homozygous LMNA p.R527C, premature aging phenotypes are recapitulated in multiple mesenchymal lineages, including mesenchymal stem cells (MSCs). Comparison with 26 human aging MSC expression datasets reveals that MAD-MSCs exhibit the highest similarity to senescent primary human MSCs. Lamina-chromatin interaction analysis reveals reorganization of lamina-associating domains (LADs) and repositioning of non-LAD binding peaks may contribute to the observed accelerated senescence. Additionally, 3D genome organization further supports hierarchical chromatin disorganization in MAD stem cells, alongside dysregulation of genes involved in epigenetic modification, stem cell fate maintenance, senescence, and geroprotection. Together, these findings suggest LMNA missense mutation is linked to chromatin alterations in an atypical progeroid syndrome.

基于椎板病的早衰症的研究提供了对衰老相关疾病的见解，并强调了 LMNA 在染色质组织中的作用。A 型下颌骶骨发育不良 （MAD） 是一种在很大程度上未被探索的非典型早衰形式，缺乏 lamin A 翻译后加工缺陷。使用源自携带纯合子 LMNA p.R527C 的男性 MAD 患者的 iPSC，在多个间充质谱系中概括了过早衰老表型，包括间充质干细胞 （MSC）。与 26 个人类衰老 MSC 表达数据集的比较表明，MAD-MSC 与衰老的原代人类 MSC 表现出最高的相似性。层-染色质相互作用分析显示，层层相关结构域 （LAD） 的重组和非 LAD 结合峰的重新定位可能导致观察到的加速衰老。此外，3D 基因组组织进一步支持 MAD 干细胞中的分层染色质杂乱，以及参与表观遗传修饰、干细胞命运维持、衰老和老年保护的基因失调。总之，这些发现表明 LMNA 错义突变与非典型早衰综合征中的染色质改变有关。