Abstract Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure. Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.

中文翻译：

---

LMNA 突变引起的脂肪营养不良综合征：生物分子方面的最新进展、病理生理学假设和治疗前景

摘要 LMNA 中的突变，编码 A 型核纤层蛋白，是造成椎板病的原因，包括肌肉营养不良、脂肪营养不良和过早衰老综合征。LMNA 突变已被证明会改变核结构和刚度、与核被膜或核质内的伴侣结合、基因表达和/或前核蛋白 A 成熟。LMNA 相关的脂肪营养不良特征，结合全身或部分脂肪萎缩和与胰岛素抵抗相关的代谢改变，可能是由脂肪细胞分化改变或脂肪结构改变引起的。最近的研究揭示了致病性 A 型 lamin 变异如何引发脂肪代谢障碍、代谢并发症和早熟心血管事件。脂肪组织细胞外基质和 TGF-β 信号的改变可能引发代谢不灵活。血管细胞的过早衰老可能导致心血管并发症。在受影响的家庭中，代谢改变发生在跨代的较早年龄，这可能是由 LMNA 突变引起的表观遗传失调所致。概括脂肪形成发育途径的新型细胞模型为疾病建模和治疗筛选提供了可扩展的工具。