Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, People's Republic of China.
Department of Neurology, Jiujiang University Clinical Medical College, Jiujiang University Hospital, Jiujiang, Jiangxi, 332000, People's Republic of China.
Biochem Genet. 2020 Dec;58(6):966-980. doi: 10.1007/s10528-020-09989-4. Epub 2020 Jul 23.
LMNA-related muscular dystrophies are caused by mutations of the LMNA gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of LMNA-related muscular dystrophies. Muscle specimen of a patient with LMNA gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in LMNA mutant cells which promoted the expression of downstream inflammatory factors. The LMNA mutation also activated the molecular pathway of apoptosis in LMNA mutant cells. These are important molecular mechanisms underlying the pathogenesis of LMNA-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for LMNA-related muscular dystrophies.
LMNA 相关肌营养不良症由 LMNA 基因突变引起。在这些患者的肌肉细胞中，炎症改变和细胞凋亡是重要的病理发现。我们旨在研究核因子-κB（NF-κB）介导的炎症作为 LMNA 相关肌营养不良症发病机制的分子机制的作用。我们之前的研究工作中报道了一位携带 LMNA 基因突变（c.1117A>G，p.I373V）患者的肌肉标本显示出明显的炎症改变。与对照组相比，肌细胞的超微结构显示出严重的核异常。因此，我们使用该突变建立了体外研究的突变细胞系。转染含有该患者突变构建体的人胚肾 293（HEK293）细胞显示出不规则的核形态。质谱分析表明基因组不稳定性和凋亡相关基因的表达增强。我们在 LMNA 突变细胞中检测到 NF-κB 通路的激活，促进了下游炎症因子的表达。LMNA 突变还激活了 LMNA 突变细胞中的凋亡分子途径。这些是 LMNA 相关肌营养不良症发病机制的重要分子机制。我们的研究为未来的发病机制研究和可能的治疗策略提供了重要证据。
