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Exonic mutations and exon skipping: Lessons learned from DFNA5 DFNA5

机译：外消除突变和外显子跳过：从DFNA5 DFNA5学习的经验教训

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摘要

Abstract Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness‐associated gene, DFNA5 , perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5‐related deafness. In five families with postlingual progressive autosomal dominant non‐syndromic hearing loss, we employed two next‐generation sequencing platforms—OtoSCOPE and whole exome sequencing—followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini‐genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5‐related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing.
机译：摘要拼接的缺点是潜在的许多遗传疾病，包括耳聋的常见因素。对于一个耳聋相关的基因，DFNA5，外显子8的扰动导致组成型活性截短的蛋白质。迄今为止，据报道，仅据报道innoric突变导致EXON 8与DFNA5相关的耳聋患者跳过。在五个家庭逐步常综合征的非综合征听力损失中，我们采用了两个下一代测序平台 - 耳镜和整个Exome测序 - 随后使用定制的生物信息学管道的次要等位基因频率和功能后果，改变滤波和优先级。在DFNA5中鉴定三种新型和两个复发性突变，在这些家庭中分离听力损失。三种新颖的突变是在外显子8内的所有麦基型变体，其计算地预测以降低拼接效率或完全废除它。我们使用携带每个突变体DFNA5外显子8的微型基因确认了它们的功能影响。在这样做中，我们在DFNA5中介绍了第一个张调突变导致耳聋，扩大DFNA5相关听力损失的突变谱，并突出了重要性评估编码变体对拼接的影响。

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  • 来源
    《Human mutation》 |2018年第3期|共8页
  • 作者

    Booth Kevin T.; Azaiez Hela; Kahrizi Kimia; Wang Donghong; Zhang Yuzhou; Frees Kathy; Nishimura Carla; Najmabadi Hossein; Smith Richard J;

  • 作者单位

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

    Genetics Research CenterUniversity of Social Welfare and Rehabilitation SciencesTehran Iran;

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

    Genetics Research CenterUniversity of Social Welfare and Rehabilitation SciencesTehran Iran;

    Department of Otolaryngology‐Head Neck SurgeryUniversity of IowaIowa City Iowa;

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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

    deafness; DFNA5; exon‐skipping; non‐syndromic hearing loss; RNA‐splicing;

    机译：耳聋;DFNA5;外来跳过;非综合征听力损失;RNA拼接;

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