Bladen Catherine L, Salgado David, Monges Soledad, Foncuberta Maria E, Kekou Kyriaki, Kosma Konstantina, Dawkins Hugh, Lamont Leanne, Roy Anna J, Chamova Teodora, Guergueltcheva Velina, Chan Sophelia, Korngut Lawrence, Campbell Craig, Dai Yi, Wang Jen, Barišić Nina, Brabec Petr, Lahdetie Jaana, Walter Maggie C, Schreiber-Katz Olivia, Karcagi Veronika, Garami Marta, Viswanathan Venkatarman, Bayat Farhad, Buccella Filippo, Kimura En, Koeks Zaïda, van den Bergen Janneke C, Rodrigues Miriam, Roxburgh Richard, Lusakowska Anna, Kostera-Pruszczyk Anna, Zimowski Janusz, Santos Rosário, Neagu Elena, Artemieva Svetlana, Rasic Vedrana Milic, Vojinovic Dina, Posada Manuel, Bloetzer Clemens, Jeannet Pierre-Yves, Joncourt Franziska, Díaz-Manera Jordi, Gallardo Eduard, Karaduman A Ayşe, Topaloğlu Haluk, El Sherif Rasha, Stringer Angela, Shatillo Andriy V, Martin Ann S, Peay Holly L, Bellgard Matthew I, Kirschner Jan, Flanigan Kevin M, Straub Volker, Bushby Kate, Verschuuren Jan, Aartsma-Rus Annemieke, Béroud Christophe, Lochmüller Hanns
The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine, University of Newcastle, Central Parkway, Newcastle upon Tyne, UK.
Hum Mutat. 2015 Apr;36(4):395-402. doi: 10.1002/humu.22758. Epub 2015 Mar 17.
Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
分析导致杜氏肌营养不良症（DMD）的患者特异性突变的类型和频率，对于诊断、基础科学研究、试验规划以及改善临床护理而言是一项极有价值的工具。位点特异性数据库有助于收集、整理、存储和分析疾病的基因变异。在此，我们描述了TREAT-NMD DMD全球数据库（http://umd.be/TREAT_DMD/）的开发与分析情况。我们分析了该数据库中收录的7149个DMD突变的基因数据。共观察到5682个大片段突变（占总突变数的80%），其中4894个（86%）为缺失突变（1个或更大外显子），784个（14%）为重复突变（1个或更大外显子）。有1445个小片段突变（小于1个外显子，占所有突变的20%），其中358个（25%）为小片段缺失，132个（9%）为小片段插入，199个（14%）影响剪接位点。点突变共有756个（占小片段突变的52%），其中726个（50%）为无义突变，30个（2%）为错义突变。最后，观察到22个（0.3%）内含子中部突变。此外，在数据库中还鉴定出了一些可能从DMD的新型基因疗法中获益的突变，包括终止密码子通读疗法（占总突变数的10%）和外显子跳跃疗法（80%的缺失突变以及55%的总突变数）。
