To determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM).

We performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the FLNC mutation were investigated with interaction and transfection studies and biophysics molecular analysis.

Eight patients revealed clinical features of slowly progressive proximal weakness associated with a heterozygous c.8025_8030delCAAGACinsA (p.K2676Pfs*3) mutation in FLNC. Two patients exhibited a mild cardiomyopathy. MRI of skeletal muscle revealed lipomatous changes typical for MFM with FLNC mutations. Muscle biopsies showed characteristic MFM findings with protein aggregation and lesion formation. The proteomic profile of aggregates was specific for MFM-filaminopathy and indicated activation of the ubiquitin-proteasome system (UPS) and autophagic pathways. Functional studies revealed that mutant FLNc is misfolded, unstable, and incapable of forming homodimers and heterodimers with wild-type FLNc.

This new MFM-filaminopathy family confirms that expression of mutant FLNC leads to an adult-onset muscle phenotype with intracellular protein accumulation. Mutant FLNc protein is biochemically compromised and leads to dysregulation of protein quality control mechanisms. Proteomic analysis of MFM protein aggregates is a potent method to identify disease-relevant proteins, differentiate MFM subtypes, evaluate the relevance of gene variants, and identify novel MFM candidate genes.

为了确定细丝蛋白 C (FLNc) 二聚化结构域中的新插入缺失突变是否会导致遗传性肌病，并伴有肌肉纤维中的蛋白质聚集，我们在临床和分子学上研究了一个患有常染色体显性肌原纤维肌病 (MFM) 的德国家族。

我们对 IM 蛋白聚集体进行了 3 代突变分析、肌肉组织病理学和蛋白质组学研究。通过相互作用和转染研究以及生物物理学分子分析研究了FLNC突变的功能后果。

8 名患者揭示了与 FLNC 中的杂合 c.8025_8030delCAAGACinsA (p.K2676Pfs*3) 突变相关的缓慢进展性近端无力的临床特征。两名患者表现出轻度心肌病。骨骼肌 MRI 显示具有FLNC突变的 MFM 的典型脂肪瘤变化。肌肉活检显示具有蛋白质聚集和病变形成的特征性 MFM 发现。聚集体的蛋白质组学特征对 MFM 丝状氨基病具有特异性，并表明泛素-蛋白酶体系统 (UPS) 和自噬途径的激活。功能研究表明，突变的 FLNc 是错误折叠的、不稳定的，并且不能与野生型 FLNc 形成同源二聚体和异源二聚体。

这个新的 MFM 丝状蛋白病家族证实突变FLNC的表达导致具有细胞内蛋白质积累的成人发病肌肉表型。突变的 FLNc 蛋白在生化方面受到损害，并导致蛋白质质量控​​制机制的失调。MFM 蛋白聚集体的蛋白质组学分析是识别疾病相关蛋白、区分 MFM 亚型、评估基因变异的相关性和识别新的 MFM 候选基因的有效方法。