Dysferlin overexpression in skeletal muscle produces a progressive myopathy.
Dysferlin overexpression in skeletal muscle produces a progressive myopathy.
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DOI：
10.1002/ana.21926
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发表时间：
2010-03
影响因子：
11.2
通讯作者：
Brown, Robert H., Jr.
中科院分区：
文献类型：
--
作者：
Glover, Louise E.;Newton, Kimberly;Krishnan, Gomathi;Bronson, Roderick;Boyle, Alexandra;Krivickas, Lisa S.;Brown, Robert H., Jr.
我们分析了异铁素转基因的剂量-反应效应，以确定异铁素缺乏性肌病是否适合基因替代治疗。我们已经培育出三种转基因小鼠，分别表达低、中、高水平的来自肌肉特异性启动子的全长人类异铁素。对转基因骨骼肌进行形态学和功能缺陷分析和评分。dysferlin在小鼠中的过度表达导致显著的后凸表型，步态不规则，肌肉质量和力量减少。此外，蛋白质剂量与表型严重程度相关。与异常蛋白缺失的骨骼肌相比，没有发现肌上皮损伤的证据。相反，与对照组相比，在转基因小鼠的肌肉裂解物中观察到Ca2+调节的异铁蛋白结合蛋白和内质网应激伴侣蛋白的水平增加。异铁素的表达水平对于正常功能而不产生有害或细胞毒性作用是重要的。因此，我们建议在未来的基因替代治疗中应该考虑到这一点。
The dose-response effects of dysferlin transgenesis were analyzed to determine if the dysferlin-deficient myopathies are good candidates for gene replacement therapy. We have generated three lines of transgenic mice, expressing low, mid and high levels of full-length human dysferlin from a muscle-specific promoter. Transgenic skeletal muscle was analyzed and scored for morphological and functional deficits. Overexpression of dysferlin in mice resulted in a striking phenotype of kyphosis, irregular gait and reduced muscle mass and strength. Moreover, protein dosage correlated with phenotype severity. In contrast to dysferlin-null skeletal muscle, no evidence of sarcolemmal impairment was revealed. Rather, increased levels of Ca2+-regulated, dysferlin-binding proteins and ER stress chaperone proteins were observed in muscle lysates from transgenic mice as compared to controls. Expression levels of dysferlin are important for appropriate function without deleterious or cytotoxic effects. As a corollary, we propose that future endeavors in gene replacement for correction of dysferlinopathy should be tailored to take account of this.
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影响因子：
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