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Open Access | 10.1172/jci.insight.172665
1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Choi, B.
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Eltawil, Y.
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Ismail Mohamad, N.
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Park, Y.
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Han, J.
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Kim, B.
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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1Department of Neurology, University of California, San Francisco, San Francisco, United States of America
2Department of Otorhinolaryngology, Seoul National University College of Medicine, Seongnam, Korea, Republic of
3Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, United States of America
4Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Korea, Republic of
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Published November 9, 2023 - More info
Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a recently described novel deafness gene in mice. Tmtc4-knockout mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair-cell-specific conditional knockout mouse that phenocopies the constitutive knockout with postnatal onset deafness, demonstrating that Tmtc4 is a hair-cell specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR towards apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.