A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy
A novel Alu-like element rearranged in the dystrophin gene causes a splicing mutation in a family with X-linked dilated cardiomyopathy
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DOI：
10.1086/301952
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发表时间：
1998-08-01
影响因子：
9.8
通讯作者：
Muntoni, F
中科院分区：
文献类型：
--
作者：
Ferlini, A;Galié, N;Muntoni, F
我们已经确定并表征了一个基因组序列，该序列具有X连锁扩张型心肌病家族中肌营养不良蛋白基因重排的类移动的元件的一些典型特征。在dystrophin基因内含子11的5'端下游2.4kb处发生了类似于dystrophin的重排。这种重排激活了内含子11中的一个隐蔽剪接位点，并产生了一个含有内含子11样序列和相邻内含子1a的一部分的替代转录物，该转录物在外显子11和12之间剪接。这种替代转录本的翻译被截短，因为在类ESTZ序列的每个框架中存在许多终止密码子。在心肌中只检测到突变mRNA，但在骨骼肌中它与正常mRNA共存。这一结果得到了免疫细胞化学结果的支持，该结果未能在患者的心肌中检测到肌营养不良蛋白，但显示骨骼肌中蛋白质表达水平降低。类似的序列的比较分析表明，与其他重复的元素，含有区域和几个表达的序列标签的高度同源性。我们认为，这种类似的序列可以代表一类新的重复元件，重复和集群与一些已知的移动的元素，并能够转座。我们的报告强调了导致X连锁扩张型心肌病的致病机制的复杂性，但表明肌营养不良蛋白突变的组织特异性表达差异可能是这种情况下的共同特征。
We have identified and characterized a genomic sequence with some features typical of Alu-like mobile elements rearranged into the dystrophin gene in a family affected by X-linked dilated cardiomyopathy. The Alu-like sequence rearrangement occurred 2.4 kb downstream from the 5' end of intron 11 of the dystrophin gene. This rearrangement activated one cryptic splice site in intron 11 and produced an alternative transcript containing the Alu-like sequence and part of the adjacent Intron la, spliced between exons 11 and 12. Translation of this alternative transcript is truncated because of the numerous stop codons present in every frame of the Alu-like sequence. Only the mutant mRNA was detected in the heart muscle, but in the skeletal muscle it coexisted with the normal one. This result is supported by the immunocytochemical findings, which failed to detect dystrophin in the patient's cardiac muscle but showed expression of a reduced level of protein in the skeletal muscle. Comparative analysis of the Alu-like sequence showed high homology with other repeated-element-containing regions and with several expressed sequence tags. We suggest that this Alu-like sequence could represent a novel class of repetitive elements, reiterated and clustered with some known mobile elements-and capable of transposition. Our report underlines the complexity of the pathogenic mechanism leading to X-linked dilated cardiomyopathy but suggests that differences in tissue-specific expression of dystrophin mutations may be a common feature in this condition.