-related congenital muscular dystrophy (L-CMD) is caused by mutations in the gene, encoding lamin A/C. To further understand the molecular mechanisms of L-CMD proteomic profiling using DIA mass spectrometry was conducted on immortalized myoblasts and myotubes from controls and L-CMD donors each harbouring a different mutation (R249W, del.32 K and L380S). Compared to controls, 124 and 228 differentially abundant proteins were detected in L-CMD myoblasts and myotubes, respectively, and were associated with enriched canonical pathways including synaptogenesis and necroptosis in myoblasts, and Huntington's disease and insulin secretion in myotubes. Abnormal nuclear morphology and reduced lamin A/C and emerin abundance was evident in all L-CMD cell lines compared to controls, while nucleoplasmic aggregation of lamin A/C was restricted to del.32 K cells, and mislocalization of emerin was restricted to R249W cells. Abnormal nuclear morphology indicates loss of nuclear lamina integrity as a common feature of L-CMD, likely rendering muscle cells vulnerable to mechanically induced stress, while differences between L-CMD cell lines in emerin and lamin A localization suggests that some molecular alterations in L-CMD are mutation specific. Nonetheless, identifying common proteomic alterations and molecular pathways across all three L-CMD lines has highlighted potential targets for the development of non-mutation specific therapies.

中文翻译：

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人类 LMNA 相关先天性肌营养不良症肌细胞的蛋白质组学特征

相关先天性肌营养不良症 (L-CMD) 是由编码核纤层蛋白 A/C 的基因突变引起的。为了进一步了解 L-CMD 蛋白质组学分析的分子机制，使用 DIA 质谱法对来自对照和 L-CMD 供体的永生化成肌细胞和肌管进行了分析，每个都含有不同的突变（R249W、del.32 K 和 L380S）。与对照相比，在 L-CMD 成肌细胞和肌管中分别检测到 124 和 228 个差异丰富的蛋白质，并且与丰富的经典途径相关，包括成肌细胞中的突触发生和坏死性凋亡，以及肌管中的亨廷顿病和胰岛素分泌。与对照相比，所有 L-CMD 细胞系均明显出现核形态异常、核纤层蛋白 A/C 和 emerin 丰度降低，而核纤层蛋白 A/C 的核质聚集仅限于 del.32 K 细胞，而 emerin 的错误定位仅限于 R249W 细胞细胞。异常的核形态表明核纤层完整性的丧失是 L-CMD 的一个共同特征，可能使肌肉细胞容易受到机械诱导的应激，而 L-CMD 细胞系之间 emerin 和核纤层蛋白 A 定位的差异表明 L-CMD 中的一些分子改变CMD 具有突变特异性。尽管如此，确定所有三个 L-CMD 系中常见的蛋白质组改变和分子途径已经突出了开发非突变特异性疗法的潜在目标。