Article record

DNAJC17调控听觉毛细胞中的RNA剪接并且是听力所必需的

DNAJC17 regulates RNA splicing in auditory hair cells and is required for hearing.

基础研究耳科IF 7.7Q1

文献信息

PMID	42869107
原文	在 PubMed 查看原文 ↗
发表日期	2026
作者	Luping Zhang 查看其他 11 位作者 Ziyang Wang；Wenya Fan；Yiliang Huang；Chenxuan Yong；Yuecen Sun；Qingyue Yuan；Guang-Jie Zhu；Ao Li；Tao Yang；Qing Liu；Guoqiang Wan
作者单位	Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, China. Electronic address: zhanglp910@126.com. 查看其他 7 条单位信息 MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China.；Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu 226001, China.；Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China.；MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.；Department of Otolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. Electronic address: yangtfxl@sina.com.；MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. Electronic address: 13585190481@163.com.；MOE Key Laboratory of Model Animal for Disease Study, Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), The Affiliated Drum Tower Hospital of Medical School and the Model Animal Research Center of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory of Molecular Medicine, National Resource Center for Mutant Mice of China, Nanjing University, Nanjing, Jiangsu 210008, China; Research Institute of Otolaryngology, No. 321 Zhongshan Road, Nanjing, Jiangsu 210008, China. Electronic address: guoqiangwan@nju.edu.cn.
期刊	Journal of genetics and genomics = Yi chuan xue bao
SCI 分区	Q1
IF	7.7
研究类型	基础研究 · 基础／转化
所属专科	耳科

中文摘要

背景： RNA剪接对基因调控至关重要，但其在维持耳蜗毛细胞功能中的作用仍不完全清楚。
方法： 在此，我们在一个多代家庭中鉴定出DNAJC17（编码剪接体相关蛋白）的一个杂合错义变异（c.401A>C，p.E134A），该变异与成年起病的进行性听力损失共分离。小鼠中毛细胞特异性敲除Dnajc17导致深度耳聋并伴有进行性毛细胞变性，确立了其在耳蜗维持中的重要作用。
结果： 缺乏DNAJC17的毛细胞表现出明显的静纤毛结构紊乱，并伴有耳蜗中广泛的可变剪接缺陷。值得注意的是，调节前体mRNA剪接的双特异性蛋白激酶Clk1显示出外显子包含改变，与剪接控制网络的破坏一致。此外，Dnajc17 p.E134A敲入小鼠出现成年起病的进行性听力损失，伴有静纤毛和线粒体异常，但保留了毛细胞存活，重现了人类表型。
结论： 总之，这些发现确定DNAJC17是常染色体显性听力损失的致病基因，并确定RNA剪接调控是耳蜗毛细胞完整性长期维持所需的关键机制。

英文摘要

RNA splicing is essential for gene regulation, but its role in maintaining cochlear hair cell function remains incompletely understood. Here, we identify a heterozygous missense variant (c.401A>C, p.E134A) in DNAJC17, which encodes a spliceosome-associated protein, that segregates with adult-onset progressive hearing loss in a multigenerational family. Hair cell-specific deletion of Dnajc17 in mice results in profound deafness with progressive hair cell degeneration, establishing its essential role in cochlear maintenance. Hair cells lacking DNAJC17 exhibit marked stereocilia disorganization accompanied by widespread alternative splicing defects in the cochlea. Notably, the dual-specificity protein kinase Clk1 that regulates pre-mRNA splicing shows altered exon inclusion, consistent with disruption of splicing control networks. In addition, Dnajc17 p.E134A knock-in mice develop adult-onset progressive hearing loss with stereocilia and mitochondrial abnormalities but preserve hair cell survival, recapitulating the human phenotype. Together, these findings identify DNAJC17 as a causative gene for autosomal dominant hearing loss and identify RNA splicing regulation as a key mechanism required for long-term maintenance of cochlear hair cell integrity.