Protein, and mRNABased phenotype-genotype correlations in DMD/DMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene
Protein, and mRNABased phenotype-genotype correlations in DMD/DMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene
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DOI：
10.1002/humu.20422
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发表时间：
2007-02-01
期刊：
影响因子：
3.9
通讯作者：
Leturcq, France
中科院分区：
文献类型：
--
作者：
Deburgrave, Nathalie;Daoud, Fatma;Leturcq, France
约 70% 的肌营养不良症涉及直接可检测的杜氏肌营养不良 (DMD) 基因重排，例如涉及整个外显子或更多的缺失或重复。剩下的 30% 被怀疑是多种点突变或“小”突变。由于其多样性以及 DMD 基因的大尺寸和复杂性，这些点突变很难检测到。为了克服这个诊断问题，我们开发并优化了基于常规肌肉活检的诊断策略。突变检出率几乎高达 100%，所有临床怀疑诊断为 DMD 和贝克尔型肌营养不良症 (BMD) 的患者均发现了突变，并通过蛋白质印迹检测定量和/或定性肌营养不良蛋白异常进一步支持了突变。在此，我们报告了在 BMD 患者中检测到的总共 124 个小突变，其中包括 11 个无义突变和移码突变。除了对肌肉表型进行全面评估（考虑突变对肌营养不良蛋白 mRNA 和蛋白质表达的影响）外，我们还提供并讨论基因组、mRNA 和蛋白质数据，以查明与无义突变和移码突变相关的 BMD 表型的分子机制。
Straightforward detectable Duchenne muscular dystrophy (DMD) gene rearrangements, such as deletions or duplications involving an entire exon or more, are involved in about 70% of dystrophinopathies. In the remaining 30% a variety of point mutations or "small" mutations are suspected. Due to their diversity and to the large size and complexity of the DMD gene, these point mutations are difficult to detect. To overcome this diagnostic issue, we developed and optimized a routine muscle biopsy-based diagnostic strategy. The mutation detection rate is almost as high as 100% and mutations were identified in all patients for whom the diagnosis of DMD and Becker muscular dystrophy (BMD) was clinically suspected and further supported by the detection on Western blot of quantitative and/or qualitative dystrophin protein abnormalities. Here we report a total of 124 small mutations including 11 nonsense and frameshift mutations detected in BMD patients. In addition to a comprehensive assessment of muscular phenotypes that takes into account consequences of mutations on the expression of the dystrophin mRNA and protein, we provide and discuss genomic, mRNA, and protein data that pinpoint molecular mechanisms underlying BMD phenotypes associated with nonsense and frameshift mutations.