Muscleblind-Like Proteins Similarities and Differences in Normal and Myotonic Dystrophy Muscle
Muscleblind-Like Proteins Similarities and Differences in Normal and Myotonic Dystrophy Muscle
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DOI：
10.2353/ajpath.2009.080520
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发表时间：
2009-01-01
影响因子：
6
通讯作者：
Morris, Glenn E.
中科院分区：
文献类型：
--
作者：
Holt, Ian;Jacquemin, Virginie;Morris, Glenn E.
在肌强直性营养不良中，肌盲样蛋白1 （MBNL1）蛋白特异性结合扩展的CUG或CCUG重复序列，这些重复序列作为离散的核病灶积累，这被认为阻碍了其调节前mrna选择性剪接的功能。有强有力的证据表明MBNL1基因在疾病病理中的作用，但两个相关基因MBNL2和MBNL3的作用尚不清楚。使用针对这三个基因产物的新的单克隆抗体，我们发现MBNL2在人类胎儿发育和成肌细胞培养过程中减少，而MBNL1不变。在杜氏肌营养不良肌中，与成熟纤维相比，MBNL2在未成熟再生纤维中的表达升高，这支持了MBNL2在发育中的作用。MBNL3仅存在于C2C12小鼠成肌细胞中。MBNL1和MBNL2在成人肌肉和肌强直性营养不良患者培养的细胞中被扩增重复序列的核灶部分隔离。在成人肌核质中，与年龄匹配的对照相比，1型肌强直性营养不良患者的这两种蛋白都减少了。在正常的人成肌细胞培养中，MBNL1和MBNL2总是共分布的，但它们的分布可以从核质到细胞质迅速变化。MBNL1和MBNL2之间的功能差异尚未被发现，可能被证明是非常微妙的。MBNL1在成熟横纹肌中的主导地位可以解释为什么仅切除小鼠MBNL1基因就足以引起肌强直性营养不良。（蚂蚁病理学杂志，2009,174:216-227;DOI: 10.2353/ajpath.2009.080520）
in myotonic dystrophy, muscleblind-like protein 1 (MBNL1) protein binds specifically to expanded CUG or CCUG repeats, which accumulate as discrete nuclear foci, and this is thought to prevent its function in the regulation of alternative splicing of pre-mRNAs. There is strong evidence for the role of the MBNL1 gene in disease pathology, but the roles of two related genes, MBNL2 and MBNL3, are less clear. Using new monoclonal antibodies specific for each of the three gene products, we found that MBNL2 decreased during human fetal development and myoblast culture, while MBNL1 was unchanged. In Duchenne muscular dystrophy muscle, MBNL2 was elevated in immature, regenerating fibres compared with mature fibres, supporting some developmental role for MBNL2. MBNL3 was found only in C2C12 mouse myoblasts. Both MBNL1 and MBNL2 were partially sequestered by nuclear foci of expanded repeats in adult muscle and cultured cells from myotonic dystrophy patients. in adult muscle nucleoplasm, both proteins were reduced in myotonic dystrophy type 1 compared with an age-matched control. in normal human myoblast cultures, MBNL1 and MBNL2 always co-distributed but their distribution could change rapidly from nucleoplasmic to cytoplasmic. Functional differences between MBNL1 and MBNL2 have not yet been found and may prove quite subtle. The dominance of MBNL1 in mature, striated muscle would explain why ablation of the mouse mbnl1 gene alone is sufficient to cause a myotonic dystrophy. (Ant J Pathol 2009, 174:216-227; DOI: 10.2353/ajpath.2009.080520)