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

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.

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Publication Details

Journal
Advanced Science
Published
2026-09-06
DOI
https://doi.org/10.1002/advs.77543
Primary Topic
Hearing, Cochlea, Tinnitus, Genetics
Type
article
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article

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

Jun Shen, Richard J. Goodyear, Thomas Haaf, Michaela A. H. Hofrichter et al.
Advanced Science
Hearing, Cochlea, Tinnitus, Genetics
article

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

Jun Shen, Richard J. Goodyear, Thomas Haaf, Michaela A. H. Hofrichter, Masato Ohtsuka, Barbara Vona, Richard T. Osgood, Paul Gratias, Artur A. Indzhykulian, Sophie Flandin, Edward J. Walsh, J. K. Saunders, Cynthia C. Morton, Evan B. Hale, Ricardo Vera-Monroy, Kerry L. Gudlewski, Guy P. Richardson, Jörg Schröder, Karen Mojica, Katherine Callahan, JoAnn McGee, Rolen Quadros, Sami S. Amr, Channabasavaiah Gurumurthy
article en

Abstract

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.

Advanced Science
Dartmouth College (US), Brigham and Women's Hospital (US), Massachusetts Eye and Ear Infirmary (US), Dartmouth–Hitchcock Medical Center (US), Nebraska Medical Center (US), Tokai University (JP), Harvard University (US), University of Sussex (GB), University of Würzburg (DE), German Primate Center (DE), Harvard University Press (US), Instituto Nicaragüense de Cultura (NI), Comprehensive Cancer Center Mainfranken (DE), Boys Town National Research Hospital (US), Universitätsmedizin Göttingen (DE), Universitätsklinikum Würzburg (DE), Mass General Brigham (US), University of Nebraska Medical Center (US), University of Göttingen (DE)
Openalex Percentile: Top 12%
Hearing, Cochlea, Tinnitus, Genetics
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