The LMNA gene encodes the A-type lamins that polymerize into ~3.5 nm thick filaments, and together with B-type lamins and lamin binding proteins form the nuclear lamina. Mutations in LMNA are associated with a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from LmnaH222P/H222P mice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filaments in situ, and using a nuclear extraction protocol. Averaging of individual segments of filaments in LmnaH222P/H222P mouse fibroblasts resolved two-polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure.

中文翻译：

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导致横纹肌疾病的层状A / C变体提供了细丝组织的见解

LMNA基因编码聚合成约3.5 nm细丝的A型纤层，并与B型纤层和纤溶酶结合蛋白一起形成核纤层。LMNA中的突变与多种病理相关。在这项研究中，我们分析了LmnaH222P / H222P小鼠胚胎成纤维细胞的核层板，它们会产生心肌病和肌肉营养不良。尽管薄层的组织看起来没有改变，但是染色质和B型薄层蛋白的表达有所变化。核尺寸的增加，以及因此层附近异染色质的相对减少，使得可以使用低温电子断层扫描技术对lamin细丝进行更高分辨率的结构分析。当现场观察层状细丝并使用核提取方案时，这一点最为明显。LmnaH222P / H222P小鼠成纤维细胞中细丝的各个片段的平均分解了构成成熟细丝的两种聚合物。我们的研究结果提供了更好的观点，对层状细丝的组织以及条纹状肌肉疾病引起的突变对核结构的影响。