Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies
Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies
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DOI：
10.1093/hmg/ddi017
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Bonne, G
中科院分区：
文献类型：
--
作者：
Arimura, T;Helbling-Leclerc, A;Bonne, G
核纤层病是由编码A型核纤层蛋白（核纤层的组分）的LMNA基因突变引起的一组疾病。其中三种疾病专门影响骨骼肌和/或心肌，其致病机制仍不清楚。我们选择了LMNA H222 P错义突变在一个常染色体显性Emery-Dreifuss肌营养不良症家族中鉴定，这是一种横纹肌特异性核纤层蛋白病，以创建这种类型核纤层蛋白病的忠实小鼠模型。突变小鼠表现出明显正常的胚胎发育和性成熟。在成年期，雄性纯合子小鼠表现出运动活动减少，具有异常僵硬的行走姿势，并且所有小鼠在9个月大时死亡。至于心脏表型，它们发展为腔室扩张和运动功能减退伴传导缺陷。在雌性纯合子小鼠中也观察到这些异常骨骼和心脏特征，但发病时间晚于雄性。对小鼠的组织学分析显示，在心脏和骨骼肌中，与异染色质移位和Smad信号传导激活相关的肌肉变性和纤维化。这些结果表明，Lmna（H222 P/H222 P）小鼠代表了用于研究影响横纹肌的核纤层蛋白病的良好模型，因为它们发展出与人类疾病相似的骨骼肌和心肌的营养不良状况。
Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that Lmna(H222P/H222P) mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases.