Filamin C-related myopathies: pathology and mechanisms.
Filamin C-related myopathies: pathology and mechanisms.
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DOI：
10.1007/s00401-012-1054-9
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发表时间：
2013-01
影响因子：
12.7
通讯作者：
van der Ven PF
中科院分区：
文献类型：
--
作者：
Fürst DO;Goldfarb LG;Kley RA;Vorgerd M;Olivé M;van der Ven PF
术语丝氨酸病是在细丝素C二聚结构域(Flnc)的截断突变被证明与一种毁灭性的肌肉疾病有关后引入的。随后，在来自不同种族的患者中发现了相同的突变，表明这种特定的改变是一个突变热点。患者最初表现为近端肌肉无力，而远端和呼吸肌随着疾病的进展而受到影响。这些患者的肌肉活检显示出肌原纤维肌病的典型征象，包括肌原纤维的解体和几种蛋白质聚集成不同的细胞内沉积物。在FLNC的Ig样结构域上有其他突变导致有毒蛋白表达的患者中也观察到了高度相似的表型。生化和生物物理研究表明，突变的结构域具有异常的结构，导致稳定性降低，最终成为与其他蛋白质异常聚集的种子。这种疾病通常在生命的第四个十年后才出现，可能是由于负责处理受损蛋白质的机制中与衰老有关的损害所致。这一点从导致高度相似表型的这种机器组件的突变中得到了证实。对培养的肌肉细胞的转基因研究反映了在患者肌肉中观察到的事件，因此，可能为测试未来的专门治疗策略提供一个有用的模型。最近，在远端肌病表型的家系中也发现了FlnC突变，这些突变要么是由于flnC的肌动蛋白结合结构域的突变导致了肌动蛋白结合的增加和非特异性的肌病异常，要么是由于杆状结构域的无义突变导致了RNA的不稳定、单倍性不足和FlnC在肌肉纤维中的表达水平降低和肌纤维异常，而不是导致诊断肌纤维病所需的desmin阳性蛋白聚集体的形成。
The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy.
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