First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Neurology. 2010 Aug 10;75(6):547-54. doi: 10.1212/WNL.0b013e3181ec7fbd.
Filamin myopathy is associated with mutations in the filamin C gene (FLNC) and is a myofibrillar myopathy characterized by focal myofibrillar destruction and cytoplasmic aggregates containing several Z-disk-related proteins.
This study investigated 6 Japanese patients with dominantly inherited myofibrillar myopathy manifested by adult-onset, slow and progressive muscle weakness and atrophy in the distal extremities.
The abundantly expressed proteins in the affected muscles were identified as filamin C by nano liquid chromatography-tandem mass spectrometry. A genetic analysis of FLNC identified a heterozygous c.8107delG mutation that was localized to the dimerization domain of filamin C. A biochemical crosslinking analysis of bacterially expressed recombinant wild-type and mutant filamin C fragments demonstrated that the mutant monomer disturbed the proper dimerization of the wild-type filamin dimer, resulting in formation of a heterotrimer with the wild-type filamin dimer. The expression study in C2C12 myoblasts showed that the mutant filamin fragments formed cytoplasmic aggregates with endogenous wild-type filamin C.
This study provides evidence for the dominant-negative effects of the FLNC mutation. These effects may be mutation-specific and likely result in the variation in the clinical phenotypes seen in patients with filamin myopathy.
Filamin 肌病与 Filamin C 基因（FLNC）的突变有关，是一种肌原纤维肌病，其特征是局灶性肌原纤维破坏和含有几种 Z 盘相关蛋白的细胞质聚集物。
本研究调查了 6 名日本患者，他们患有显性遗传性肌原纤维肌病，表现为成年起病、缓慢进行性的四肢远端肌无力和萎缩。
通过纳升液相色谱-串联质谱法，在受累肌肉中鉴定出大量表达的蛋白为 Filamin C。FLNC 的基因分析发现了一个杂合 c.8107delG 突变，该突变定位于 Filamin C 的二聚化结构域。细菌表达的重组野生型和突变型 Filamin C 片段的生化交联分析表明，突变型单体干扰了野生型 Filamin 二聚体的正确二聚化，导致与野生型 Filamin 二聚体形成杂三聚体。在 C2C12 成肌细胞中的表达研究表明，突变型 Filamin 片段与内源性野生型 Filamin C 形成细胞质聚集物。
本研究提供了 FLNC 突变具有显性负效应的证据。这些效应可能是突变特异性的，可能导致 Filamin 肌病患者临床表型的变化。
