Article record

TECTB变异揭示显性非综合征性听力损失中盖膜脆弱性

TECTB Variants Reveal Tectorial Membrane Vulnerability in Dominant Non-Syndromic Hearing Loss.

基础研究耳科IF 15.6Q1

文献信息

PMID	42702881
原文	在 PubMed 查看原文 ↗
发表日期	2026
作者	Evan B Hale 查看其他 23 位作者 Barbara Vona；Richard J Goodyear；Richard T Osgood；Jun Shen；Sami S Amr；Karen Mojica；Michaela A H Hofrichter；Jörg Schröder；Sophie Flandin；Paul Gratias；Ricardo Vera-Monroy；Katherine Callahan；Kerry L Gudlewski；Rolen Quadros；Masato Ohtsuka；JoAnn McGee；Edward J Walsh；Cynthia C Morton；Thomas Haaf；Channabasavaiah Gurumurthy；James E Saunders；Guy P Richardson；Artur A Indzhykulian
作者单位	Mass Eye and Ear, Eaton Peabody Laboratories, Boston, Massachusetts, USA. 查看其他 17 条单位信息 Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA.；Speech and Hearing Bioscience and Technology Program, Harvard University, Cambridge, Massachusetts, USA.；Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Göttingen, Germany.；Auditory Neuroscience and Optogenetics Laboratory, German Primate Center, Göttingen, Germany.；Collaborative Research Center 1690 (CRC1690), University of Göttingen, Göttingen, Germany.；Sussex Neuroscience, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.；Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.；Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.；Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, Massachusetts, USA.；Department of Otolaryngology, Vivian Pellas Hospital, Managua, Nicaragua.；Institute of Clinical Genetics and Genome Medicine, University Hospital Würzburg, Würzburg, Germany.；Institute of Human Genetics, Julius-Maximilians-University Würzburg, Würzburg, Germany.；Department of Otolaryngology, Comprehensive Hearing Center, University Clinics, Würzburg, Germany.；Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.；Mouse Genome Engineering Core Facility, Nebraska Medical Center, Omaha, Nebraska, USA.；Division of Basic Medical Science and Molecular Medicine, School of Medicine, Tokai University, Kanagawa, Japan.；Developmental Auditory Physiology Laboratory, Boys Town National Research Hospital, Omaha, Nebraska, USA.
期刊	Advanced science (Weinheim, Baden-Wurttemberg, Germany)
SCI 分区	Q1
IF	15.6
研究类型	基础研究 · 基础／转化
所属专科	耳科

中文摘要

尽管进行了全面的基因检测，许多非综合征性听力损失患者仍缺乏分子诊断，因此识别新的致病基因仍是一个关键目标。盖膜（TM）是内耳特化的无细胞基质，对于刺激机械敏感毛细胞静纤毛束以及维持频率调谐和听觉敏感性至关重要。虽然编码TM中几种非胶原蛋白的基因（TECTA、CEACAM16、OTOG、OTOGL）的突变已被确定为耳聋基因，但尚无明确证据表明β-盖膜蛋白（TECTB）与之相关。在此，我们提出了多条遗传学和实验证据，将TECTB的杂合错义变异（NM_058222.3:c.674G>A, p.Cys225Tyr 和 NM_058222.3:c.853C>T, p.Arg285Cys）与听力损失联系起来。每个变异都影响透明带结构域内或直接侧翼的高度保守残基。使用Tectb-C225Y敲入小鼠模型，我们发现纯合动物表现出严重的听力损失和TM形态的严重破坏，而杂合动物尽管听觉阈值正常，但TM内染色密度降低，且对噪声诱导的听力损失易感性增加。这些发现确定了TECTB是一个新的人类耳聋基因，进一步阐明了其在维持TM完整性和抵抗环境相关听觉衰退中的作用。

英文摘要

Identifying new genes responsible for non-syndromic hearing loss remains a critical goal as many patients still lack a molecular diagnosis despite comprehensive genetic testing. The tectorial membrane (TM) is a specialized acellular matrix of the inner ear, essential for stimulating mechanosensitive hair cell stereocilia bundles and maintaining frequency tuning and auditory sensitivity. Although mutations in genes encoding several non-collagenous proteins found in the TM (TECTA, CEACAM16, OTOG, OTOGL) have been identified as deafness genes, definitive evidence implicating β-tectorin (TECTB) has been lacking. Here, we present multiple lines of genetic and experimental evidence linking heterozygous missense variants in TECTB (NM_058222.3:c.674G>A, p.Cys225Tyr and NM_058222.3:c.853C>T, p.Arg285Cys), with hearing loss. Each variant affects highly conserved residues within or directly flanking the zona pellucida domain. Using a Tectb-C225Y knock-in mouse model, we show that homozygous animals exhibit severe hearing loss and profound disruption of TM morphology, while heterozygous animals display decreased staining density within the TM and increased susceptibility to noise-induced hearing loss, despite normal auditory thresholds. These findings identify TECTB as a novel human deafness gene, further elucidate its contribution to maintaining TM integrity and resilience against environmentally-related auditory decline.