A nonsense mutation-created intraexonic splice site is active in the lymphocytes, but not in the skeletal muscle of a DMD patient
A nonsense mutation-created intraexonic splice site is active in the lymphocytes, but not in the skeletal muscle of a DMD patient
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DOI：
10.1007/s00439-006-0241-y
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发表时间：
2007-01-01
期刊：
影响因子：
5.3
通讯作者：
Matsuo, Masafumi
中科院分区：
文献类型：
--
作者：
Tran, Van Khanh;Takeshima, Yasuhiro;Matsuo, Masafumi
从编码提前终止密码子的dystrophin基因产生半功能性dystrophin mRNA已被证明可以改变Duchenne肌营养不良症(DMD)的严重表型。在这项研究中，我们报道了通过激活无义突变产生的外显子内剪接受体位点，组织特异性地产生半功能性dystrophin mRNA。在1例DMD患者中，在42号外显子中发现了一种新的无义突变。在他的淋巴细胞中，发现了外显子42缺失63个核苷酸的半功能性dystrophin mRNA(dys-63)。利用杂交微基因的体外剪接实验表明，突变产生的外显子内剪接受体位点被激活。然而，在他的骨骼肌细胞中，只发现了真正剪接的dystrophin mRNA。这一发现确定了DMD病例中肌营养不良蛋白mRNA剪接的调节，作为治疗策略的潜在靶点，以产生该疾病的较温和的表型。
Production of semi-functional dystrophin mRNA from the dystrophin gene encoding a premature stop codon has been shown to modify the severe phenotype of Duchenne muscular dystrophy (DMD). In this study, we report the tissue-specific production of semi-functional dystrophin mRNA via activation of a nonsense mutation-created intraexonic splice acceptor site. In a DMD patient a novel nonsense mutation was identified in exon 42. In his lymphocytes semi-functional dystrophin mRNA with a 63-nucleotide deletion in exon 42 (dys-63) was found to be produced. In vitro splicing assay using hybrid minigenes disclosed that the mutation-created intraexonic splice acceptor site was activated. In his skeletal muscle cells, however, only the authentically spliced dystrophin mRNA was found. This finding identifies the modulation of the splicing of muscle dystrophin mRNA in cases of DMD as a potential target for therapeutic strategies to generate a milder phenotype for this disease.