Heterogous Dystrophin mRNA Produced by a Novel Splice Acceptor Site Mutation in Intermediate Dystrophinopathy
Heterogous Dystrophin mRNA Produced by a Novel Splice Acceptor Site Mutation in Intermediate Dystrophinopathy
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中间型肌营养不良蛋白病中新型剪接受体位点突变产生的异源肌营养不良蛋白 mRNA
DOI：
10.1203/00006450-200301000-00021
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发表时间：
2003
影响因子：
3.6
通讯作者：
M. Matsuo
中科院分区：
文献类型：
--
作者：
Kayo Adachi;Y. Takeshima;H. Wada;M. Yagi;Hajime Nakamura;M. Matsuo
一种中间型肌营养不良症[Duchenne和Becker肌营养不良症(DMD/BMD)]的分子背景尚不清楚，dystrophin基因的框外突变和框内突变分别是导致DMD和BMD的原因。应用逆转录聚合酶链式反应(RT-PCR)对1例男童的外周血淋巴细胞和肌肉中提取的抗肌营养不良蛋白基因进行了定性和定量分析。在基因内含子20的保守剪接受体位点上发现了3个隐含的剪接受体位点，其中一个在外显子20和21(dys+6)之间插入了内含子20的6个核苷酸，编码了dystrophin杆状结构域中的两个新的氨基酸。另外两种基因在20号外显子20和21号外显子之间插入了7个核苷酸(dys+7)，或21号外显子有7个核苷酸缺失(dys−7)。对男孩骨骼肌中每种dystrophin基因的定量分析表明，约95%和5%的dystrophin基因分别是dys−7和dys+6，而这两种基因在淋巴细胞中的表达几乎相同。这表明，肌肉中一小部分框内mRNA的产生解释了指征病例中中间型营养不良的分子背景。这一发现强调了基因治疗策略的潜力，该策略旨在修改DMD的mRNA，以产生一种温和得多的疾病。
The molecular background of an intermediate type of dystrophinopathy [Duchenne and Becker muscular dystrophy (DMD/BMD)] remains to be clarified, and out-of -frame and in-frame mutations of the dystrophin gene are shown to be causes of DMD and BMD, respectively. In a boy with this disease, dystrophin mRNA extracted from lymphocytes and muscle were analyzed both qualitatively and quantitatively using reverse transcription PCR. Three different dystrophin mRNA were found to be produced via the use of three cryptic splice acceptor sites resulting from a novel point mutation of 2831-2A>G at the conserved splice acceptor site of intron 20. One of three mRNA showed an insertion of six nucleotides of intron 20 between exons 20 and 21 (dys+6) that encoded two novel amino acids in the rod domain of dystrophin. Two other mRNA species showed an insertion of seven nucleotides of intron 20 between exons 20 and 21 (dys+7) or a seven-nucleotide deletion in exon 21 (dys−7). Quantitative analysis of each dystrophin mRNA expressed in the boy's skeletal muscle disclosed that around 95% and 5% of dystrophin mRNAs were dys−7 and dys+6, respectively, whereas these two mRNA were almost equally expressed in lymphocytes. It is suggested that production of a small fraction of in-frame mRNA in muscle explains the molecular background of the intermediate type of dystrophinopathy in the index case. This finding underlines the potential of genetic therapeutic strategies aimed to modify mRNA in DMD to generate a much milder disease.
影响因子：
9.8
作者：
Schwarze, U;Starman, BJ;Byers, PH
通讯作者：
Byers, PH
影响因子：
4.4
作者：
Monaco, Anthony P.;Bertelson, Corlee J.;Kunkel, Louis M.
通讯作者：
Kunkel, Louis M.