Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.
Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies.
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DOI：
10.1186/s40478-022-01400-0
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发表时间：
2022-07-09
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
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杆状体肌病（NM）是一种具有广泛临床和遗传异质性的肌肉疾病。受累个体的临床表现从严重的围产期肌无力到较轻微的儿童期发病形式不等，疾病进程和预后取决于基因和突变类型。到目前为止，已经确定了14个致病基因，其中ACTA1占严重NM病例的一半以上。ACTA1编码α -肌动蛋白，它是骨骼肌收缩单位的主要成分之一。我们建立了一个由10个未报道的严重NM家庭组成的同质队列，并提供了临床、遗传、组织学和超微结构数据。患者表现出产前或新生儿肌无力，需要永久性呼吸辅助，且大多数在出生后的头几个月内死亡。DNA测序在所有病例中都发现了已知或新的ACTA1突变。肌肉活检标本的形态学分析显示了NM组织病理学的特征，包括细胞质和细胞核内的杆状体、细胞质体以及主要的肌原纤维紊乱。我们还检测到核周间隙的结构异常，强调了骨骼肌α -肌动蛋白对细胞核形状的生理作用。对细胞核的深入研究证实了核纤层蛋白A/C、内斯普林 - 1和内斯普林 - 2的异常定位，它们是核纤层和LINC复合物的主要成分，确保核膜的完整性。为了验证我们研究结果的相关性，我们检查了3例先前报道的ACTA1病例的肌肉样本，并发现了相同的一组结构畸变。此外，我们测量到寿命较长的患者肌肉样本中心脏α -肌动蛋白表达增加，这表明可能存在一种代偿效应。总体而言，这项研究扩展了严重ACTA1相关杆状体肌病的遗传和形态学谱，改进了分子诊断，强调核周间隙扩大是一种超微结构特征，并指出了一种潜在的基因型/表型相关性。
在线版本包含补充材料，可在10.1186/s40478 - 2022 - 01400 - 0获取。
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. The online version contains supplementary material available at 10.1186/s40478-022-01400-0.
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DOI：
10.1083/jcb.76.1.146
发表时间：
1978-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
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通讯作者：
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影响因子：
1.9
作者：
Ladha, Shafeeq;Coons, Stephen;Sivakumar, Kumaraswamy
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影响因子：
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作者：
Lornage, Xaviere;Quijano-Roy, Susana;Bohm, Johann
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影响因子：
2.8
作者：
Munot, P.;Lashley, D.;Muntoni, F.
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Muntoni, F.
DOI：
10.1016/j.nmd.2017.02.012
发表时间：
2017-06
期刊：
Neuromuscular disorders : NMD
影响因子：
--
作者：
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通讯作者：
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