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ResearchIn-Press PreviewOtology Open Access | 10.1172/jci.insight.172665

TMTC4 is a hair-cell-specific human deafness gene

Jiang Li,1 Byung Yoon Choi,2 Yasmin Eltawil,3 Noura Ismail Mohamad,3 Yesai Park,3 Ian R. Matthews,3 Jin-Hee Han,2 Bong Jik Kim,4 Elliott H. Sherr,1 and Dylan K. Chan3

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

Find articles by Li, J. in: JCI | PubMed | Google Scholar

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

Find articles by Choi, B. in: JCI | PubMed | Google Scholar |

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

Find articles by Eltawil, Y. in: JCI | PubMed | Google Scholar |

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

Find articles by Ismail Mohamad, N. in: JCI | PubMed | Google Scholar |

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

Find articles by Park, Y. in: JCI | PubMed | Google Scholar |

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

Find articles by Matthews, I. in: JCI | PubMed | Google Scholar

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

Find articles by Han, J. in: JCI | PubMed | Google Scholar |

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

Find articles by Kim, B. in: JCI | PubMed | Google Scholar |

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

Find articles by Sherr, E. in: JCI | PubMed | Google Scholar

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

Find articles by Chan, D. in: JCI | PubMed | Google Scholar

Published November 9, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.172665.
Copyright © 2023, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 9, 2023 - Version history
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Abstract

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.

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