Myofibrillar myopathy caused by novel dominant negative αB-crystallin mutations
Myofibrillar myopathy caused by novel dominant negative αB-crystallin mutations
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DOI：
10.1002/ana.10767
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发表时间：
2003-12-01
影响因子：
11.2
通讯作者：
Engel, AG
中科院分区：
文献类型：
--
作者：
Selcen, D;Engel, AG
我们在这里报告的第二和第三个突变的α-晶体蛋白引起肌原纤维肌病。两名患者有成人发作的肌无力。患者1有颈部、肢带和呼吸肌无力，死于呼吸衰竭。患者2有近端和远端腿部肌肉无力。两人都有肌病肌电图与异常电刺激和肌肉活检结果的肌原纤维肌病和轻度去神经。肌原纤维崩解开始于Z盘，并导致结蛋白、晶状体蛋白、肌营养不良蛋白、神经细胞粘附分子（NCAM）和CDC 2激酶的异常局部表达。7 - 8%的细胞核显示早期凋亡变化。两名患者均在α-晶状体蛋白的C-末端区域携带截短突变（患者1中的464 delCT和患者2中的Q151 X），这对于分子的溶解和伴侣功能至关重要。cDNA分析显示相同的突变，没有选择性剪接的转录本。肌肉的免疫印迹显示野生型蛋白表达增加，突变蛋白表达减少。非变性条件下的免疫印迹显示，突变蛋白与野生型形成低于正常分子量的多聚体复合物。我们的结论是：（1）尽管其表达减少，突变蛋白发挥了显性负效应;（2）α-晶体蛋白突变是肌原纤维肌病的罕见原因;（3）α-晶体蛋白相关肌病表现出表型异质性。
We here report the second and third mutations in alphabeta-crystallin causing myofibrillar myopathy. Two patients had adult-onset muscle weakness. Patient 1 had cervical, limb girdle, and respiratory muscle weakness and died of respiratory failure. Patient 2 had proximal and distal leg muscle weakness. Both had myopathic electromyogram with abnormal electrical irritability and muscle biopsy findings of myofibrillar myopathy and mild denervation. Myofibrillar disintegration begins at the Z-disk and results in abnormal local expression of desmin, alphabeta-crystallin, dystrophin, neural cell adhesion molecule (NCAM), and CDC2 kinase. Seven to 8% of nuclei display early apoptotic changes. Both patients carry a truncating mutation in the C-terminal region of alphabeta-crystallin (464delCT in Patient 1 and Q151X in Patient 2) which is crucial for the solubilization and chaperone functions of the molecule. cDNA analysis shows the same mutations and no alternatively spliced transcripts. Immunoblots of muscle demonstrate increased expression of wild-type and reduced expression of the mutant protein. Immunoblots under nondenaturing conditions show that the mutant protein forms lower than normal molecular weight multimeric complexes with wild type. We conclude that (1) despite its reduced expression, the mutant protein exerts a dominant negative effect; (2) mutations in alphabeta-crystallin are an infrequent cause of myofibrillar myopathy; (3) alphabeta-crystallin-related myopathies display phenotypic heterogeneity.