Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery-Dreifuss Muscular Dystrophy
Lamin A/C Assembly Defects in LMNA-Congenital Muscular Dystrophy Is Responsible for the Increased Severity of the Disease Compared with Emery-Dreifuss Muscular Dystrophy
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DOI：
10.3390/cells9040844
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发表时间：
2020-04-01
期刊：
影响因子：
6
通讯作者：
Bonne, Gisele
中科院分区：
文献类型：
--
作者：
Bertrand, Anne T.;Brull, Astrid;Bonne, Gisele
LMNA 编码核纤层蛋白 A/C，即 V 型中间丝，在内核膜下聚合形成核纤层。一小部分核纤层蛋白 A/C（聚合程度较低）也存在于核质中。 Lamin A/C 功能包括核抗机械应力和基因调控的作用。 LMNA 突变导致多种病理，包括没有明确基因型-表型相关性的 Emery-Dreifuss (EDMD) 和 LMNA 相关先天性肌营养不良症 (L-CMD)。这两种疾病均表现为横纹肌疾病，尽管 L-CMD 症状出现得更早且更严重。为了寻找病理力学差异来解释 L-CMD 突变的严重性，我们对 UMD-LMNA 数据库进行了计算机分析，发现 L-CMD 突变主要影响涉及核纤层蛋白二聚体和四聚体稳定性的残基。与此相符，我们发现与对照和 EDMD 相比，L-CMD 患者成纤维细胞和小鼠成肌细胞中核质核纤层蛋白 A/C 增加。 L-CMD 成肌细胞表现出分化缺陷，与其无法上调肌肉特异性核膜 (NE) 蛋白表达有关。 NE 蛋白定位错误，导致细胞核畸形。我们得出的结论是，这些缺陷是由于核纤层中缺乏核纤层蛋白 A/C 及其在肌管核质中的维持所致。
LMNA encodes for Lamin A/C, type V intermediate filaments that polymerize under the inner nuclear membrane to form the nuclear lamina. A small fraction of Lamin A/C, less polymerized, is also found in the nucleoplasm. Lamin A/C functions include roles in nuclear resistance to mechanical stress and gene regulation. LMNA mutations are responsible for a wide variety of pathologies, including Emery-Dreifuss (EDMD) and LMNA-related congenital muscular dystrophies (L-CMD) without clear genotype-phenotype correlations. Both diseases presented with striated muscle disorders although L-CMD symptoms appear much earlier and are more severe. Seeking for pathomechanical differences to explain the severity of L-CMD mutations, we performed an in silico analysis of the UMD-LMNA database and found that L-CMD mutations mainly affect residues involved in Lamin dimer and tetramer stability. In line with this, we found increased nucleoplasmic Lamin A/C in L-CMD patient fibroblasts and mouse myoblasts compared to the control and EDMD. L-CMD myoblasts show differentiation defects linked to their inability to upregulate muscle specific nuclear envelope (NE) proteins expression. NE proteins were mislocalized, leading to misshapen nuclei. We conclude that these defects are due to both the absence of Lamin A/C from the nuclear lamina and its maintenance in the nucleoplasm of myotubes.