Abstract
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.
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Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. All data relevant to the study are included in the article.
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Acknowledgements
The authors appreciated all the grant supports that enabled this research. This work was sponsored by the National Key Research and Development Program of China (No. 2016YFC0901505); National Natural Science Foundation of China (No. 81571220); Bei**g key laboratory of molecular diagnosis and study on pediatric genetic diseases (No. BZ0317); Peking University Medicine Seed Fund for Interdisciplinary Research supported by the Fundamental Research Funds for the Central Universities (No. BMU2017MX003, BMU2018MX001); Natural Science Foundation of Jiangxi Province (No. 20161BAB215192).
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Yanbin Fan conducted the experiments and wrote the first draft of the manuscript. Danyu Song, Lin Ge, Haipo Yang, and Jianxin Liu took part in the experiments and data analysis. Xu Zhang and Suxia Wang analyzed the muscle cell ultrastructure of the patients. Dandan Tan constructed lentiviral vectors expressing LMNA wild-type or mutant-type (c.1117A>G, p.I373V). **ngzhi Chang, Shuang Wang, and Hui Yan provided advice to the manuscript. Carsten Bonnemann, **ru Wu, Hong Zhang, and Hui **ong took part in study design, experiments and critical discussions. Hong Zhang, and Hui **ong conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors participated in drafting and critically revising the article and approved the final manuscript.
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The study was approved by the Ethics Committee of Peking University First Hospital (No. 2015[916], Bei**g, China).
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Informed written consent was obtained from the patient and her legal guardians.
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Fan, Y., Tan, D., Zhang, X. et al. Nuclear Factor-κB Pathway Mediates the Molecular Pathogenesis of LMNA-Related Muscular Dystrophies. Biochem Genet 58, 966–980 (2020). https://doi.org/10.1007/s10528-020-09989-4
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DOI: https://doi.org/10.1007/s10528-020-09989-4