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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >Three novel types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences
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Three novel types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences

机译：结节性共有序列以外的突变导致结节性硬化性TSC2基因的三种新型剪接畸变

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Disease causing aberrations in both tuberous sclerosis predisposing genes, TSC1 and TSC2, comprise nearly every type of alteration with a predominance of small truncating mutations distributed over both genes. We performed an RNA based screening of the entire coding regions of both TSC genes applying the protein truncation test (PTT) and identified a high proportion of unusual splicing abnormalities affecting the TSC2 gene. Two cases exhibited different splice acceptor mutations in intron 9 (IVS9-15G → A and IVS9-3C → G) both accompanied by exon 10 skipping and simultaneous usage of a cryptic splice acceptor in exon 10. Another splice acceptor mutation (IVS38-18A → G) destroyed the putative polypyrimidine structure in intron 38 and resulted in simultaneous intron retention and usage of a downstream cryptic splice acceptor in exon 39. Another patient bore a C → T transition in intron 8 (IVS8+281C → T) activating a splice donor site and resulting in the inclusion of a newly recognised exon in the mRNA followed by a premature stop. These splice variants deduced from experimental results are additionally supported by RNA secondary structure analysis based on free energy minimisation. Three of the reported splicing anomalies are due to sequence changes remote from exon/intron boundaries, described for the first time in TSC. These findings highlight the significance of investigating intronic changes and their consequences on the mRNA level as disease causing mutations in TSC.
机译：TSC1和TSC2这两个结节性硬化症易感基因中引起疾病​​的畸变几乎包括每种类型的改变，并且主要分布在两个基因上的小截短突变。我们应用蛋白质截断测试（PTT）对两个TSC基因的整个编码区进行了基于RNA的筛选，并确定了影响TSC2基因的异常剪接异常的比例很高。两种情况在内含子9中表现出不同的剪接受体突变（IVS9-15G→A和IVS9-3C→G），均伴有外显子10的跳跃，同时在外显子10中同时使用了隐秘的剪接受体。另一个剪接受体突变（IVS38-18A→ G）破坏了内含子38中假定的聚嘧啶结构，并导致内含子同时保留并使用了外显子39中的下游隐性剪接受体。另一名患者在内含子8中经历了C→T转变（IVS8 + 281C→T），从而激活了剪接供体位点并导致在mRNA中包含新识别的外显子，然后过早终止。从实验结果推导出的这些剪接变体还受到基于自由能最小化的RNA二级结构分析的支持。 TSC中首次描述了三个报告的剪接异常是由于远离外显子/内含子边界的序列变化。这些发现突出了研究内含子变化及其对mRNA水平的影响的重要性，这些变化是疾病导致TSC突变的原因。

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