计算机三维重构验证Dystrophin疏水区段与Duchenne型肌营养不良的发病(英文)  

Effects of the dystrophin hydrophobic regions in the pathogenesis of Duchenne muscular dystrophy A three-dimensional reconstruction verification

作　　者：梁颖茵[1] 操基清[1] 杨娟[2] 张成[1] 

机构地区：[1]中山大学附属第一医院,广东省广州市510000 [2]南方医科大学珠江医院神经内科,广东省广州市510000

出　　处：《中国组织工程研究》2013年第50期8703-8711,共9页Chinese Journal of Tissue Engineering Research

摘　　要：背景:Duchenne型肌营养不良和Becker型进行性肌营养不良都是dystrophin基因突变所致,但后者临床表型较轻。"阅读框规则"可解释大部分基因型与临床型关系,但累及疏水区段的整码突变也可导致Duchenne型肌营养不良。因此很有必要了解疏水区域在dystrophin中的功能,且这些疏水区段的三维结构及功能在发病机制中所起的具体作用仍未阐明。目的:通过Kyte&Doolittle平均疏水轮廓分析研究dystrophin的疏水区段。利用swiss-model三维重构dystrophin的疏水区段阐述其在发病机制中所起的作用。方法:参考莱顿开放数据库(http://www.dmd.nl/)及收集中山大学附属第一医院2002年至2013年确诊Duchenne型进行性肌营养不良或Becker型进行性肌营养不良的缺失型整码突变患者资料共1 038例,分析其临床型与基因型关系。使用bioedit软件计算dystrophin的平均疏水轮廓及利用swiss-model三维重构疏水区段,结合临床型和基因型关系确定dystrophin重要功能区。结果与结论:dystrophin存在4个疏水区段,分别为肌动蛋白结合区内的Calponin同源区2、中央棒区内的重复区16、第三铰链区和EF手型区。第1,2,4疏水区段是dystrophin糖蛋白复合物中dystrophin与其他糖蛋白的结合区域,其破坏严重影响dystrophin糖蛋白复合物功能,临床症状重。中央棒区在第三铰链区附近断裂后,HⅢ的无规则卷结构不容易与断端重复区的螺旋结构恢复连接。但第三铰链区同时缺失,其两端的重复区较容易重新连接,所以第3疏水区破坏后其临床症状反而较轻。提示dystrophin的疏水区段是其重要功能区,多是dystrophin糖蛋白复合物中dystrophin与相关蛋白的结合部位,在Duchenne型肌营养不良的发病机制中起重要作用。BACKGROUND： Duchenne muscular dystrophy is recognized as a fatal X-linked recessive inheritance. It is caused by the dystrophin gene mutation, resulting in the deficiency of dystrephin and consequent degeneration and necrosis of muscle fibers gradually. Backer muscular dystrophy is also caused by the mutation of the same gene, but presented with less severe clinical symptoms compared with Duchenne muscular dystrophy. Frameshift mutation destroys the reading frames, and thus the translation cannot proceed smoothly to transcript functional proteins. In-frame mutation cannot destroy the reading frames and hence the translation can proceed smoothly. But in-frame mutation involves the whole hydrophobic regions. The three-dimensional structure of these regions and their functionality are not interpreted clearly. The effects of these regions on disease development need to be clarified in detail from the point of structure and function. OBJECTIVE： By analyzing Kate and Dolittle scale mean hydrophobicity profile, to investigate the dystrophin hydrophobic regions using Swiss-model so as to provide the supplement explanation on the reading frame rule. METHODS： Form 2002 to 2013, 1 038 cases diagnosed as Duchenne muscular dystrophy or Backer muscular dystrophy were collected in the First Hospital of Sun Yat-sen University in China and Leiden DMD information database was searched with deletion of codon mutation information available. The correlation between clinical types and genotypes was analyzed upon resources collected above. The mean hydrophobicity profile of dystrophin was analyzed by Bioedit as well as the reconstruction of hydrophobic domains using Swiss-model. Thus, the important functional domain of dystrophin was confirmed by analysis and the correlation between clinical types and genotypes. RESULTS AND CONCLUSION： Four hydrophobic regions were confirmed： Calponin homology domain CH2 on actin-binding domain, repeat 16 domain, Hinge III domain and EF Hand domain. Duchenne muscular dystrophy was developed a

关 键 词：组织构建 组织构建基础实验 DUCHENNE型肌营养不良 Becker型进行性肌营养不良 DYSTROPHIN Kyte&Doolittle疏水轮廓分析 三维结构 bioedit SWISS-MODEL 基因型-临床型分析 

分 类 号：R318[医药卫生—生物医学工程]