Evan B Hale, 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
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.