神经肌病(NM)是一种具有广泛临床和遗传异质性的肌肉疾病。受影响个体的临床表现范围从严重的围产期肌无力到较温和的儿童期发作形式,病程和预后取决于基因和突变类型。迄今为止,已经确定了14个致病基因,ACTA1占严重NM病例的一半以上。ACTA1编码α-肌动蛋白,骨骼肌收缩单位的主要成分之一。我们建立了一个由10个未报告的重度NM家庭组成的同质队列,我们提供临床,遗传,组织学,和超微结构数据。患者表现出产前或新生儿肌肉无力,需要永久性呼吸辅助,大多数人在生命的头几个月内死亡。DNA测序鉴定了所有已知或新的ACTA1突变。肌肉活检标本的形态学分析显示NM组织病理学的特征,包括细胞质和核内棒,细胞质体,和严重的肌原纤维紊乱。我们还检测到核周空间的结构异常,强调骨骼肌α-肌动蛋白对核形状的生理贡献。对细胞核的深入研究证实了层板蛋白A/C的异常定位,Nesprin-1和Nesprin-2,形成核层和LINC复合物的主要成分,并确保核包膜的完整性。为了验证我们发现的相关性,我们检查了先前报道的3例ACTA1病例的肌肉样本,我们确定了同一组结构像差。此外,我们测量了寿命较长的患者的肌肉样本中心脏α-肌动蛋白的表达增加,表明潜在的补偿效应。总的来说,这项研究扩展了严重ACTA1相关的线虫肌病的遗传和形态学谱,改善分子诊断,强调核周空间的扩大是超微结构的标志,并表明潜在的基因型/表型相关性。
Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and
ACTA1 accounts for more than half of the severe NM cases.
ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel
ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported
ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe
ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.