Nemaline myopathy caused by mutations in the muscle α-skeletal-actin gene
Nemaline myopathy caused by mutations in the muscle α-skeletal-actin gene
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DOI：
10.1086/320605
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发表时间：
2001-06-01
影响因子：
9.8
通讯作者：
North, KN
中科院分区：
文献类型：
--
作者：
Ilkovski, B;Cooper, ST;North, KN
线状体肌病（NM）是一种临床和遗传异质性疾病，其特征在于肌无力和骨骼肌中存在线状体（杆）。致病突变已在五个基因中报道，每个基因编码肌节细丝的蛋白质组分。最近，我们在一组NM患者中发现了肌肉α-肌动蛋白基因（ACTA 1）的突变。在本研究中，我们评估了一个新的系列的35例NM患者。我们在ACTA 1中发现了5个新的错义突变，这表明肌肉α-骨骼肌动蛋白的突变导致了15%的NM患者的疾病。突变从头出现，代表新的显性突变。一个先证者随后有两个受影响的孩子，结果与常染色体显性遗传一致。这7名患者表现出明显的临床变异性，从严重的先天性虚弱，在生命的第一年死于呼吸衰竭，到轻度的儿童期发病的肌病，存活到成年。有显着的变化，在发病年龄和临床严重程度在一个家庭的三个成员。共同的病理特征包括异常的纤维类型分化，糖原积累，肌原纤维中断，和肌动蛋白细丝的“螺纹状”。与杆的纤维的百分比与临床严重程度无关，但是，严重的，致命的表型与严重的，广泛的肌节结构紊乱和肌节肌动蛋白的异常定位。ACTA 1不同突变的患者在临床表型上的显著差异表明，突变位点和氨基酸变化的性质对细丝形成和蛋白质-蛋白质相互作用具有不同的影响。家族内的变异性表明α-肌动蛋白基因型不是表型的唯一决定因素.
Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder characterized by muscle weakness and the presence of nemaline bodies (rods) in skeletal muscle. Disease-causing mutations have been reported in five genes, each encoding a protein component of the sarcomeric thin filament. Recently, we identified mutations in the muscle alpha -skeletal-actin gene (ACTA1) in a subset of patients with NM. In the present study, we evaluated a new series of 35 patients with NM. We identified five novel missense mutations in ACTA1, which suggested that mutations in muscle alpha -skeletal actin account for the disease in similar to 15% of patients with NM. The mutations appeared de novo and represent new dominant mutations. One proband subsequently had two affected children, a result consistent with autosomal dominant transmission. The seven patients exhibited marked clinical variability, ranging from severe congenital-onset weakness, with death from respiratory failure during the 1st year of life, to a mild childhood-onset myopathy, with survival into adulthood. There was marked variation in both age at onset and clinical severity in the three affected members of one family. Common pathological features included abnormal fiber type differentiation, glycogen accumulation, myofibrillar disruption, and "whorling" of actin thin filaments. The percentage of fibers with rods did not correlate with clinical severity; however, the severe, lethal phenotype was associated with both severe, generalized disorganization of sarcomeric structure and abnormal localization of sarcomeric actin. The marked variability, in clinical phenotype, among patients with different mutations in ACTA1 suggests that both the site of the mutation and the nature of the amino acid change have differential effects on thin-filament formation and protein-protein interactions. The intrafamilial variability suggests that alpha -actin genotype is not the sole determinant of phenotype.