DMD Exon 1 Truncating Point Mutations: Amelioration of Phenotype by Alternative Translation Initiation in Exon 6
DMD Exon 1 Truncating Point Mutations: Amelioration of Phenotype by Alternative Translation Initiation in Exon 6
复制标题
DOI：
10.1002/humu.20913
复制
发表时间：
2009-04-01
期刊：
影响因子：
3.9
通讯作者：
Flanigan, Kevin M.
中科院分区：
文献类型：
--
作者：
Gurvich, Olga L.;Maiti, Baijayanta;Flanigan, Kevin M.
DMD基因突变导致两种与进行性肌无力相关的常见表型：更严重的杜氏肌营养不良症（DMD）和更温和的贝克肌营养不良症（BMD）。我们以前已经确定了DMD基因的第一个外显子内的无义突变（c.9G>A; p.Trp3X），编码肌营养不良蛋白的427 kDa肌肉同种型的独特N-末端。虽然这种突变会导致严重的疾病，但临床表型是非常轻微的BMD，并保持到第七个十年。我们确定了负责改善疾病严重程度的分子机制是在外显子6内的两个邻近AUG密码子处启动翻译。大的突变数据集的分析表明，这可能是一个表型拯救的DMD基因的至少前两个外显子内的点突变的一般机制。我们的研究结果直接证明，第一次，使用替代翻译起始密码子内的DMD基因，并表明，肌营养不良蛋白缺乏氨基酸编码的前五个外显子保留显着的功能。《Mutat》30，633-640，2009年。(C)2009 Wiley-Liss，Inc.
Mutations in the DMD gene result in two common phenotypes associated with progressive muscle weakness: the more severe Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy (BMD). We have previously identified a nonsense mutation (c.9G>A; p.Trp3X) within the first exon of the DMD gene, encoding the unique N-terminus of the 427-kDa muscle isoform of the dystrophin protein. Although this mutation would be expected to result in severe disease, the clinical phenotype is very mild BMD, with ambulation preserved into the seventh decade. We identify the molecular mechanism responsible for the amelioration of disease severity to be initiation of translation at two proximate AUG codons within exon 6. Analysis of large mutational data sets suggests that this may be a general mechanism of phenotypic rescue for point mutations within at least the first two exons of the DMD gene. Our results directly demonstrate, for the first time, the use of alternate translational initiation codons within the DMD gene, and suggest that dystrophin protein lacking amino acids encoded by the first five exons retains significant function. Hum Mutat 30, 633-640, 2009. (C) 2009 Wiley-Liss, Inc.