Filamin C (encoded by the FLNC gene) is a large actin‐cross‐linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z‐discs of cross‐striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal‐dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild‐type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild‐type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.

中文翻译：

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FLNC 先天性发病和纯合突变的肌原纤维肌病的首次临床和肌病理学描述。

细丝蛋白C（由FLNC基因编码）是一种大的肌动蛋白交联蛋白，参与塑造肌动蛋白细胞骨架，以响应横纹肌细胞的肌膜和肌原纤维 Z 盘的信号事件。FLNC 的多个突变与常染色体显性遗传的肌原纤维肌病有关。在这里，我们首次描述了一个先天性全身性肌张力减退和肌肉无力、运动发育延迟但没有与纯合FLNC相关的心脏受累的男孩突变 c.1325C>G (p.Pro442Arg)。我们对显性丝蛋白病的已知标记蛋白进行了超形态学、蛋白质组学和功能研究以及免疫学研究。我们表明突变蛋白的表达量与对照骨骼肌纤维中的野生型变体相似。股四头肌的蛋白质组学特征发生改变，超微结构扰动明显。此外，细丝蛋白病标记蛋白在我们的纯合子和显性对照病例 (c.5161delG) 中都具有可比性。生化研究表明，与野生型变体相比，重组突变蛋白稳定性较差，更容易被蛋白水解酶降解。该疾病不寻常的先天性表现清楚地表明FLNC突变的纯合性 严重加重表型。