...
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Increased activity of Diaphanous homolog 3 (DIAPH3)I diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila
【24h】

Increased activity of Diaphanous homolog 3 (DIAPH3)I diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila

机译:透色的透明同系物3(DIAPH3)I的活动增加会导致听觉神经病患者和果蝇的听力障碍

获取原文
获取原文并翻译 | 示例
           

摘要

Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant non-syndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G > A, g. 48G > A mutation in a highly conserved region of the 5' UTR. The c.-172G > A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (≈1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G > A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitu-tively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyn-dromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy.
机译:听觉神经病是一种罕见的耳聋形式,其特征是听觉脑干反应缺失或异常,并保留了外部毛细胞功能。我们已经确定透照同源物3(DIAPH3)是负责常染色体显性非综合征性听觉神经病(AUNA1)的基因,我们先前将其定位于染色体13q21-q24。其他家族成员的基因分型将间隔缩小到仅包含四个基因(包括DIAPH3)的11-Mb,3.28-cM基因贫乏区域。 DIAPH3的DNA测序显示c.-172G> A,g。 48G> 5'UTR高度保守区域的突变。 c.-172G> A突变发生在GC盒序列元素内,在379个对照中未发现。使用全基因组表达阵列和定量RT-PCR,我们证明了受影响个体的淋巴母细胞细胞系中DIAPH3 mRNA的2至3倍过表达。同样,通过定量免疫印迹得自受影响个体的成淋巴细胞样细胞系的裂解物,与对照相比,DIAPH3蛋白显着增加(约1.5倍)。另外,c.-172G> A突变足以驱动萤光素酶报道分子的过表达。最后,在果蝇的听觉器官中透明性蛋白的组成型活性形式的表达概括了对声音响应受损的表型。迄今为止,已知只有两个基因,即otoferlin基因OTOF和pejvakin基因PJVK,是非综合征性听觉神经病的基础。 DIAPH3的基因检测可能对非症状性听觉神经病的隐性和显性遗传个体有用。

著录项

  • 来源
  • 作者单位

    Neuroscience Graduate Program, Department of Otolaryngology- Head and Neck Surgery Molecular & Behavioral Neuroscience Institute, Department of Otolaryngology- Head and Neck Surgery;

    rnDivision of Pediatric Otolaryngology, Department of Otolaryngology- Head and Neck Surgery;

    rnDivision of Pediatric Otolaryngology, Department of Otolaryngology- Head and Neck Surgery;

    rnDepartments of Cell Biology and Anatomy and New York Medical College, Valhalla, NY 10595;

    rnMolecular & Behavioral Neuroscience Institute, Department of Otolaryngology- Head and Neck Surgery;

    rnDivision of Pediatric Otolaryngology, Department of Otolaryngology- Head and Neck Surgery;

    rnDepartments of Cell and Developmental Biology, University of Michigan Health System, Ann Arbor, MI 48109;

    rnDepartments of Cell Biology and Anatomy and New York Medical College, Valhalla, NY 10595 Departments of Otolaryngology, New York Medical College, Valhalla, NY 10595;

    rnMolecular & Behavioral Neuroscience Institute, Department of Otolaryngology- Head and Neck Surgery Departments of Human Genetics, University of Michigan Health System, Ann Arbor, MI 48109 Departments of Psychiatry, University of Michigan Health System, Ann Arbor, MI 48109;

    rnDivision of Pediatric Otolaryngology, Department of Otolaryngology- Head and Neck Surgery;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    genetics; 5'UTR; formin; overexpression; DIAPH1;

    机译:遗传学5'UTR;福明过度表达膜片1;

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号