Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.

中文翻译：

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与肌原纤维肌病相关的p.W2710X丝蛋白C变体的纯合表达揭示了肌节病变形成的主要机制。

Filamin C（FLNc）主要在横纹肌细胞中表达，其位于Z盘，肌腱接头和椎间盘之间。最近的研究表明，FLNC基因中的许多突变会导致家族性和散发性肌病和心肌病，并具有明显的临床变异性。最常见的肌病性突变p.W2710X与肌原纤维肌病相关，从FLNc中删除了羧基末端的16个氨基酸，并取消了Ig样结构域24的二聚化特性。我们以前对“敲入”小鼠的特征是杂合这种突变（p.W2711X），现在已经使用蛋白和mRNA表达分析，质谱以及广泛的免疫定位和超微结构研究对纯合小鼠进行了研究。尽管后一种小鼠在正常情况下表现出相对较轻的肌病，我们的分析确定了导致该疾病病理生理的主要机制：与野生型动物相比（i）FLNc蛋白的表达水平大大降低；（ii）突变的FLNc从Z盘重新定位到肌肉细胞特别机械拉伸的部分，即肌腱连接和肌原纤维病变；（iii）病变的数量大大增加，并且这些病变缺乏与Bcl2相关的致癌基因3（BAG3）蛋白；（iv）热休克蛋白β-7（HSPB7）的表达几乎完全被消除。这些发现表明严重的BAG3依赖性和非依赖性自噬途径被有效修复病变所需要。此外，我们的研究揭示了病变形成的一般机制，并证明了有缺陷的FLNc通过其羧基末端结构域的二聚化不会干扰肌原纤维的组装和基本功能。另一个位于氨基末端的二聚化位点可能会弥补这一损失。由于纤维蛋白起着应力传感器的作用，我们的数据进一步证实了FLNc对于Z盘稳定和维护中的机械传感很重要。