Actin nemaline myopathy mouse reproduces disease, suggests other actin disease phenotypes and provides cautionary note on muscle transgene expression.
Actin nemaline myopathy mouse reproduces disease, suggests other actin disease phenotypes and provides cautionary note on muscle transgene expression.
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DOI：
10.1371/journal.pone.0028699
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Nowak KJ
中科院分区：
文献类型：
--
作者：
Ravenscroft G;Jackaman C;Sewry CA;McNamara E;Squire SE;Potter AC;Papadimitriou J;Griffiths LM;Bakker AJ;Davies KE;Laing NG;Nowak KJ
骨骼肌α-肌动蛋白基因（ACTA1）突变可引起先天性肌病，包括线状肌病、肌动蛋白聚集性肌病和棒核病。大多数ACTA1突变的患者有严重的低张力，不能活过1岁。建立了一种表达ACTA1常染色体显性突变体（D286G）与EGFP融合的转基因小鼠模型（在一名严重线状肌病患者中发现）。在多个骨骼肌中观察到线状体，连续切片显示这些与突变骨骼肌α-肌动蛋白- egfp的聚集相关。离体指长伸肌和比目鱼肌在4周龄时明显弱于野生型（WT）肌肉，与结构性病变的峰值一致。这些4周大的小鼠在自主跑轮上的活跃程度比WT小鼠低30%。α-actin-EGFP蛋白清楚地表明，在出生后早期，转基因在所有肌球蛋白重链（MHC）纤维类型中表达相同，但随后主要局限于MHCIIB纤维。经常观察到环状纤维、内核和肌纤维肌病病理，而不是线状肌病或ACTA1突变患者的典型特征。Ringbinden在成年小鼠的快纤维优势肌肉中发现，并且完全是mhciib阳性纤维。因此，该小鼠模型为研究线虫体形成和肌肉无力的病理生物学以及评估潜在的治疗干预措施提供了可靠的模型。核样区，内核和环结的发生将允许分析这些病变的机制。在ACTA1疾病小鼠模型中ringbinder的发生和肌纤维肌病的特征提示，具有这些病理且没有遗传解释的患者应筛查ACTA1突变。
Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies including nemaline myopathy, actin aggregate myopathy and rod-core disease. The majority of patients with ACTA1 mutations have severe hypotonia and do not survive beyond the age of one. A transgenic mouse model was generated expressing an autosomal dominant mutant (D286G) of ACTA1 (identified in a severe nemaline myopathy patient) fused with EGFP. Nemaline bodies were observed in multiple skeletal muscles, with serial sections showing these correlated to aggregates of the mutant skeletal muscle α-actin-EGFP. Isolated extensor digitorum longus and soleus muscles were significantly weaker than wild-type (WT) muscle at 4 weeks of age, coinciding with the peak in structural lesions. These 4 week-old mice were ∼30% less active on voluntary running wheels than WT mice. The α-actin-EGFP protein clearly demonstrated that the transgene was expressed equally in all myosin heavy chain (MHC) fibre types during the early postnatal period, but subsequently became largely confined to MHCIIB fibres. Ringbinden fibres, internal nuclei and myofibrillar myopathy pathologies, not typical features in nemaline myopathy or patients with ACTA1 mutations, were frequently observed. Ringbinden were found in fast fibre predominant muscles of adult mice and were exclusively MHCIIB-positive fibres. Thus, this mouse model presents a reliable model for the investigation of the pathobiology of nemaline body formation and muscle weakness and for evaluation of potential therapeutic interventions. The occurrence of core-like regions, internal nuclei and ringbinden will allow analysis of the mechanisms underlying these lesions. The occurrence of ringbinden and features of myofibrillar myopathy in this mouse model of ACTA1 disease suggests that patients with these pathologies and no genetic explanation should be screened for ACTA1 mutations.
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影响因子：
9.8
作者：
Ilkovski, B;Cooper, ST;North, KN
通讯作者：
North, KN
影响因子：
--
作者：
Jackaman, Connie;Nowak, Kristen J.;Laing, Nigel G.
通讯作者：
Laing, Nigel G.
影响因子：
2.8
作者：
Jungbluth, H;Sewry, CA;Muntoni, F
通讯作者：
Muntoni, F
影响因子：
5.5
作者：
BROOKS, SV;FAULKNER, JA
通讯作者：
FAULKNER, JA
影响因子：
12.4
作者：
Dunant, P;Larochelle, N;Lochmüller, H
通讯作者：
Lochmüller, H