Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.

通过深度表型分析和高通量测序，我们发现了一种由 X 连锁小肌肉蛋白 ( SMPX ) 突变引起的新型远端肌病。) 基因。在来自五个不同国家的九个家庭的十名患者中发现了四种不同的错义突变，这表明这种疾病也可能在其他人群中流行。对具有相似血统的患者的单倍型分析揭示了南欧和法国的两种不同的创始人突变，表明这些人群中的患病率可能更高。在我们的研究中，所有患者都表现出高度相似的临床特征：成人起病，通常远端肢体肌肉无力多于近端肢体肌肉无力，数十年来缓慢进展，并保留步行。下肢肌肉成像显示肌肉受累和脂肪变性的特征性模式。对患者肌肉活检的组织病理学和电子显微镜分析显示，肌病发现有边缘空泡和肌浆包涵体，其中一些具有淀粉样蛋白样特征。计算机预测和随后的细胞培养研究表明，错义突变增加了 SMPX 蛋白的聚集倾向。在细胞培养研究中，过表达的 SMPX 定位于应激颗粒并减慢它们的清除速度。