The pathogenesis of ACTA1-related congenital fiber type disproportion
The pathogenesis of ACTA1-related congenital fiber type disproportion
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DOI：
10.1002/ana.21112
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发表时间：
2007-06-01
影响因子：
11.2
通讯作者：
North, Kathryn
中科院分区：
文献类型：
--
作者：
Clarke, Nigel F.;Ilkovski, Biljana;North, Kathryn
目的：ACTAI突变与肌肉组织学的各种变化有关，这些变化可能是由于ACTAI突变破坏肌肉功能的方式存在根本差异。最近，我们报道了3例先天性纤维类型失调（CFTD）患者，由ACTAI （D292V, L221P, P332S）的新型杂合错义突变引起，肌肉活检的唯一病理发现是明显的I型纤维萎缩。我们研究了这些CFTD患者和ACTAI神经性肌病（NM）患者之间组织学差异的基础。方法与结果：质谱分析和双向凝胶电泳显示，突变型肌动蛋白分别占P332S和D292V突变患者骨骼肌α -骨骼肌动蛋白的25%和50%，符合显性t阴性发病机制。体外运动研究表明，肌动蛋白和原肌凝蛋白之间的异常相互作用可能是D292V肌无力的主要原因，原肌凝蛋白稳定在“关闭”位置。在电子显微镜下，D292V和P322S CFTD突变都与正常的肌肉结构相关，这对于严重的NM来说是不典型的。相比之下，我们发现在C2C12表达模型中，与NM和CFTD相关的ACTAI突变在聚合或聚集倾向方面没有明显差异。解释：这些数据表明，ACTAI CFTD突变通过破坏肌节功能而不是结构导致肌节虚弱。我们认为，当突变的肌动蛋白融入肌瘤时，结构紊乱的存在与否可能是ACTAI肌病中CFTD或NM的组织学模式发展的重要决定因素。
Objective: Mutations in ACTAI have been associated with a variety of changes in muscle histology that likely result from fundamental differences in the way that ACTAI mutations disrupt muscle function. Recently, we reported three patients with congenital fiber type disproportion (CFTD) caused by novel heterozygous missense mutations in ACTAI (D292V, L221P, P332S) with marked type I Fiber hypotrophy as the only pathological finding on muscle biopsy. We have investigated the basis for the histological differences between these CFTD patients and patients with ACTAI nernaline myopathy (NM).Methods and Results: Mass spectrometry and two-dimensional gel electrophoresis demonstrate that mutant actin accounts for 25 and 50% of alpha-skeletal actin in the skeletal muscle of patients with the P332S and D292V mutations, respectively, consistent with a dominan t- negative disease mechanism. In vitro motility studies indicate that abnormal interactions between actin and tropomyosin are the likely principal cause of muscle weakness for D292V, with tropomyosin stabilized in the "switched off' position. Both the D292V and P322S CFTD mutations are associated with normal sarcomeric structure on electron microscopy, which is atypical for severe NM. In contrast, we found no clear difference between ACTAI mutations associated with NM and CFTD in tendency to polymerize or aggregate in C2C12 expression models.Interpretation: These data suggest that ACTAI CFTD mutations cause weakness by disrupting sarcomere function rather than structure. We raise the possibility that the presence or absence of structural disorganization when mutant actin incorporates into sarcomeres may be an important determinant of whether the histological patterns of CFTD or NM develop in ACTAI myopathy.