β-Thalassemia Due to Intronic LINE-1 Insertion in the β-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the β-GlobinL1 Allele
β-Thalassemia Due to Intronic LINE-1 Insertion in the β-Globin Gene (HBB): Molecular Mechanisms Underlying Reduced Transcript Levels of the β-GlobinL1 Allele
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DOI：
10.1002/humu.22383
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发表时间：
2013-10-01
期刊：
影响因子：
3.9
通讯作者：
Divoky, Vladimir
中科院分区：
文献类型：
--
作者：
Lanikova, Lucie;Kucerova, Jana;Divoky, Vladimir
我们描述了 (+)-地中海贫血的分子病因学，该病是由全长转座元件 LINE-1 (L1) 插入 -珠蛋白基因 (HBB) 的内含子 2 引起的。受影响的β珠蛋白基因的转录水平严重降低。剩余的转录本由全长、正确加工的β-球蛋白mRNA和微量的三个异常剪接的转录本组成，由于无义介导的衰变途径的激活，半衰期缩短。 β-珠蛋白 (L1) 等位基因产生的 mRNA 稳态量较低也是由于转录速率降低和全长 β-珠蛋白初级转录物的产生减少所致。 -球蛋白(L1)等位基因的启动子和增强子序列被高甲基化；然而，用去甲基化剂治疗并不能恢复受损的转录。尽管 β-珠蛋白 (L1) 启动子 CpG 甲基化，但组蛋白脱乙酰酶抑制剂仍部分重新激活 β-珠蛋白 (L1) 转录。该结果表明 -globin(L1) 等位基因转录率的降低与染色质结构的改变有关。因此，β-珠蛋白基因中内含子L1插入引起的分子缺陷代表了β-地中海贫血的新病因。 (C) 2013 年 Wiley 期刊公司。
We describe the molecular etiology of (+)-thalassemia that is caused by the insertion of the full-length transposable element LINE-1 (L1) into the intron-2 of the -globin gene (HBB). The transcript level of the affected -globin gene was severely reduced. The remaining transcripts consisted of full-length, correctly processed -globin mRNA and a minute amount of three aberrantly spliced transcripts with a decreased half-life due to activation of the nonsense-mediated decay pathway. The lower steady-state amount of mRNA produced by the -globin(L1) allele also resulted from a reduced rate of transcription and decreased production of full-length -globin primary transcripts. The promoter and enhancer sequences of the -globin(L1) allele were hypermethylated; however, treatment with a demethylating agent did not restore the impaired transcription. A histone deacetylase inhibitor partially reactivated the -globin(L1) transcription despite permanent -globin(L1) promoter CpG methylation. This result indicates that the decreased rate of transcription from the -globin(L1) allele is associated with an altered chromatin structure. Therefore, the molecular defect caused by intronic L1 insertion in the -globin gene represents a novel etiology of -thalassemia. (C) 2013 Wiley Periodicals, Inc.