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首页> 外文期刊>Journal of Molecular Biology >Identification of novel alternative splicing events in the huntingtin gene and assessment of the functional consequences using structural protein homology modelling.
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Identification of novel alternative splicing events in the huntingtin gene and assessment of the functional consequences using structural protein homology modelling.

机译：鉴定亨廷顿基因中新的可变剪接事件，并使用结构蛋白同源性建模评估功能后果。

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Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by a pathological CAG trinucleotide repeat expansion in the large multi-exon gene, huntingtin (HTT). Although multiple pathogenic mechanisms have been proposed for HD, there is increasing interest in the RNA processing of the HTT gene. In mammals, most multi-exon genes are alternatively spliced; however, few alternative transcripts have been described for HTT. Given the numerous protein bands detected in mouse and human brain tissue by Western blotting using anti-huntingtin antibodies, we examined whether alternative splicing of HTT may account for some of these fragments. Using RT-PCR in mouse brain, we detected two novel splice variants of Htt that lacked the 111-bp exon 29 (Htt?ex29) or retained a 57-bp portion of intron 28 (Htt(+57)in28) via use of a cryptic splice site. The alternative transcripts were present in wild-type and homozygous Hdh(Q150/Q150) mouse brain at all ages and in all brain regions and peripheral tissues studied. Differential splicing of Htt?ex29 was found in the cerebellum of Hdh(Q150/Q150) mice with a significant reduction in transcript levels in mutant animals. In human brain, we detected similar splice variants lacking exons 28 and 29. The ability of alternatively spliced transcripts to encode different protein isoforms with individual functions in the cell, combined with the known role of splicing in disease, renders these novel transcripts of interest in the context of HD pathogenesis.
机译：亨廷顿舞蹈病（HD）是一种遗传性进行性神经退行性疾病，由大型多外显子基因huntingtin（HTT）中的病理CAG三核苷酸重复扩增引起。尽管针对HD提出了多种致病机制，但是人们对HTT基因的RNA处理越来越感兴趣。在哺乳动物中，大多数多外显子基因是可变剪接的。但是，关于HTT的替代转录本很少见。鉴于使用抗亨廷顿抗体通过蛋白质印迹在小鼠和人脑组织中检测到大量蛋白条带，我们检查了HTT的可变剪接是否可以解释其中的某些片段。在小鼠脑中使用RT-PCR，我们检测到了两个新的Htt剪接变体，它们缺少111bp外显子29（Htt？ex29）或保留了内含子28（Htt（+57）in28）的57bp部分一个神秘的拼接站点。替代转录本存在于各个年龄段的野生型和纯合Hdh（Q150 / Q150）小鼠脑中，并且在研究的所有脑区域和外围组织中均存在。在Hdh（Q150 / Q150）小鼠小脑中发现了Htt？ex29的差异剪接，突变动物的转录水平显着降低。在人脑中，我们检测到了缺少外显子28和29的相似剪接变体。选择性剪接的转录本编码细胞中具有个别功能的不同蛋白质同工型的能力，加上已知的在疾病中的剪接作用，使得这些新的转录本受到关注。 HD发病机制的背景。

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