Université de Rennes, Rennes, France.
Orphanet J Rare Dis. 2012 Jul 9;7:45. doi: 10.1186/1750-1172-7-45.
Dystrophin is a large essential protein of skeletal and heart muscle. It is a filamentous scaffolding protein with numerous binding domains. Mutations in the DMD gene, which encodes dystrophin, mostly result in the deletion of one or several exons and cause Duchenne (DMD) and Becker (BMD) muscular dystrophies. The most common DMD mutations are frameshift mutations resulting in an absence of dystrophin from tissues. In-frame DMD mutations are less frequent and result in a protein with partial wild-type dystrophin function. The aim of this study was to highlight structural and functional modifications of dystrophin caused by in-frame mutations.
We developed a dedicated database for dystrophin, the eDystrophin database. It contains 209 different non frame-shifting mutations found in 945 patients from a French cohort and previous studies. Bioinformatics tools provide models of the three-dimensional structure of the protein at deletion sites, making it possible to determine whether the mutated protein retains the typical filamentous structure of dystrophin. An analysis of the structure of mutated dystrophin molecules showed that hybrid repeats were reconstituted at the deletion site in some cases. These hybrid repeats harbored the typical triple coiled-coil structure of native repeats, which may be correlated with better function in muscle cells.
This new database focuses on the dystrophin protein and its modification due to in-frame deletions in BMD patients. The observation of hybrid repeat reconstitution in some cases provides insight into phenotype-genotype correlations in dystrophin diseases and possible strategies for gene therapy. The eDystrophin database is freely available: http://edystrophin.genouest.org/.
肌营养不良蛋白是骨骼肌和心肌的重要大型蛋白。它是一种带有许多结合域的丝状支架蛋白。DMD 基因（编码肌营养不良蛋白）的突变主要导致一个或多个外显子缺失，从而导致杜氏肌营养不良症（DMD）和贝克肌营养不良症（BMD）。最常见的 DMD 突变是导致组织中肌营养不良蛋白缺失的移码突变。框内 DMD 突变则较少见，导致具有部分野生型肌营养不良蛋白功能的蛋白。本研究旨在强调框内突变引起的肌营养不良蛋白的结构和功能改变。
我们开发了一个专门的肌营养不良蛋白数据库，即 eDystrophin 数据库。它包含了来自法国队列和先前研究的 945 名患者中的 209 种不同的非移码突变。生物信息学工具提供了缺失部位蛋白三维结构的模型，使我们能够确定突变蛋白是否保留肌营养不良蛋白典型的丝状结构。对突变肌营养不良蛋白分子结构的分析表明，在某些情况下，缺失部位会重新构建杂种重复。这些杂种重复含有天然重复的典型三螺旋卷曲结构，这可能与肌肉细胞中更好的功能相关。
这个新的数据库主要关注 BMD 患者肌营养不良蛋白及其因框内缺失而产生的改变。在某些情况下观察到杂种重复的重新构建，为肌营养不良蛋白疾病的表型-基因型相关性以及基因治疗的可能策略提供了新的见解。eDystrophin 数据库可免费获取：http://edystrophin.genouest.org/。
