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首页> 外文期刊>Human mutation >Modified U1 snRNA and antisense oligonucleotides rescue splice mutations in SLC26A4 SLC26A4 that cause hereditary hearing loss
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Modified U1 snRNA and antisense oligonucleotides rescue splice mutations in SLC26A4 SLC26A4 that cause hereditary hearing loss

机译：修饰的U1 SnRNA和反义寡核苷酸在SLC26A4 SLC26A4中拯救剪接突变，导致遗传性听力损失

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摘要

Abstract One of most important factors for messenger RNA (mRNA) transcription is the spliceosomal component U1 small nuclear RNA (snRNA), which recognizes 5′ splicing donor sites at specific regions in pre‐mRNA. Mutations in these sites disrupt U1 snRNA binding and cause abnormal splicing. In this study, we investigated mutations at splice sites in SLC26A4 (HGNC 8818), one of the major causative genes of hearing loss, which may result in the synthesis of abnormal pendrin, the channel protein encoded by the gene. Seventeen SLC26A4 variants with mutations in the U1 snRNA binding sites were assessed by minigene splicing assays, and 11 were found to result in abnormal splicing. Interestingly, eight of the 11 pathogenic mutations were intronic, suggesting the importance of conserved sequences at the intronic splice site. The application of modified U1 snRNA effectively rescued the abnormal splicing for most of these mutations. Although three were cryptic mutations, they were rescued by cotransfection of modified U1 snRNA and modified antisense oligonucleotides. Our results demonstrate the important role of snRNA in SLC26A4 mutations, suggesting the therapeutic potential of modified U1 snRNA and antisense oligonucleotides for neutralizing the pathogenic effect of the splice‐site mutations that may result in hearing loss.
机译：摘要信使RNA（mRNA）转录中最重要的因素之一是抗乳糖体组分U1小核RNA（SNRNA），其识别在前mRNA前特定区域的5'剪接供体部位。这些位点中的突变破坏U1 SnRNA结合并导致异常剪接。在该研究中，我们研究了SLC26A4（HGNC 8818）中的接头位点的突变，听力损失的主要致病基因之一，这可能导致异常的pendrin，由基因编码的通道蛋白质。通过小烯剪接测定评估具有U1 SnRNA结合位点中的突变的17个SLC26A4变体，发现11个导致剪接异常。有趣的是，11个致病性突变中的八个是内血管内的，表明在内文剪接部位的保守序列的重要性。改性U1 SnRNA的应用有效地拯救了大多数这些突变的异常剪接。虽然三个是神秘的突变，但它们被修饰的U1 SnRNA和修饰的反义寡核苷酸的Cot转染救出。我们的结果表明SnRNA在SLC26A4突变中的重要作用，表明修饰的U1 SnRNA和反义寡核苷酸的治疗潜力，用于中和可能导致听力损失的致密性突变的致病效果。

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  • 来源
    《Human mutation》 |2019年第8期|共9页
  • 作者

    Lee Byeonghyeon; Kim Ye‐Ri; Kim Sang‐Joo; Goh Sung‐Ho; Kim Jong‐Heun; Oh Se‐Kyung; Baek Jeong‐In; Kim Un‐Kyung; Lee Kyu‐Yup;

  • 作者单位

    Department of Biology College of Natural SciencesKyungpook National UniversityDaegu Republic of;

    Department of Biology College of Natural SciencesKyungpook National UniversityDaegu Republic of;

    Department of Biology College of Natural SciencesKyungpook National UniversityDaegu Republic of;

    Therapeutic Target Discovery BranchNational Cancer CenterGoyang‐si Gyeonggi‐do Republic of Korea;

    Department of Biology College of Natural SciencesKyungpook National UniversityDaegu Republic of;

    Laboratory Animal CenterDaegu‐Gyeongbuk Medical Innovation FoundationDaegu Republic of Korea;

    Department of Aroma‐Applied IndustryDaegu Haany UniversityGyeongsan Republic of Korea;

    Department of Biology College of Natural SciencesKyungpook National UniversityDaegu Republic of;

    Department of Otorhinolaryngology‐Head and Neck Surgery School of MedicineKyungpook National;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学遗传学;
  • 关键词

    antisense oligonucleotide; SLC26A4; splicing; splicing correction; U1 snRNA;

    机译：反义寡核苷酸;SLC26A4;拼接;拼接矫正;U1 SNRNA;

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