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Cited by 61Hearing, Cochlea, Tinnitus, GeneticsEndoplasmic Reticulum Stress and DiseaseIon Channels and Receptors

Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss

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Li, Jiang, Akil, Omar, Rouse, Stephanie L., McLaughlin, Conor W., Matthews, Ian R., Lustig, Lawrence R., Chan, Dylan K., Sherr, Elliott H.·2018·Journal of Clinical Investigation
DOI 10.1172/jci97498PMC PMC6205388
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Abstract

Hearing loss is a significant public health concern, affecting over 250 million people worldwide. Both genetic and environmental etiologies are linked to hearing loss, but in many cases the underlying cellular pathophysiology is not well understood, highlighting the importance of further discovery. We found that inactivation of the gene Tmtc4 (transmembrane and tetratricopeptide repeat 4), which was broadly expressed in the mouse cochlea, caused acquired hearing loss in mice. Our data showed Tmtc4 enriched in the endoplasmic reticulum, and that it functioned by regulating Ca2+ dynamics and the unfolded protein response (UPR). Given this genetic linkage of the UPR to hearing loss, we demonstrated a direct link between the more common noise-induced hearing loss (NIHL) and the UPR. These experiments suggested a novel approach to treatment. We demonstrated that the small-molecule UPR and stress response modulator ISRIB (integrated stress response inhibitor), which activates eIF2B, prevented NIHL in a mouse model. Moreover, in an inverse genetic complementation approach, we demonstrated that mice with homozygous inactivation of both Tmtc4 and Chop had less hearing loss than knockout of Tmtc4 alone. This study implicated a novel mechanism for hearing impairment, highlighting a potential treatment approach for a broad range of human hearing loss disorders.

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  • CG4050 is a mammalian ortholog of TMTC3, one of a family of ER proteins recently shown to be O-mannosyltransferases; deletion of TMTC3 causes neurological defects.

    “CG4050 is a mammalian ortholog of TMTC3, one of a family of ER proteins recently shown to be O-mannosyltransferases; deletion of TMTC3 causes neurological defects [61,62].”

    From Functional unknomics: Systematic screening of conserved genes of unknown function (2023) · cites this paper as [62]

    The discussion reports that TMTC proteins may participate in an O-mannosylation pathway, but describes this as a suggestion rather than showing that they are O-mannosyltransferases. The cited paper studies Tmtc4; our copy does not establish a CG4050–TMTC3 orthology or report neurological defects from TMTC3 deletion. No page number is available for the discussion passage. (LLM, conf=0.83)

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Cited by

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Authors
Li, J., Akil, O., Rouse, S. L., McLaughlin, C. W., Matthews, I. R., Lustig, L. R., Chan, D. K., & Sherr, E. H.
Affiliations
  • University of California, San Francisco (US)
  • NewYork–Presbyterian Hospital (US)
Corresponding author
  • Chan, Dylan K.
  • Sherr, Elliott H.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2018-10-15
Volume
128
Issue
11
Pages
5150-5162
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci97498
PMC
PMC6205388
OpenAlex
W2891828956
Cited by
61
References
0
Citations by year
2026: 8 · 2025: 3 · 2024: 16 · 2023: 11 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 5
FWCI
3.23
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
NIH Office of the Director (2R01NS058721,R03DC015082,UL1TR001872)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Hearing, Cochlea, Tinnitus, Genetics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
unfolded protein response, noise-induced hearing loss, cochlea, endoplasmic reticulum, calcium dynamics, ISRIB, eIF2B, CHOP, integrated stress response, complementation, hereditary hearing loss
MeSH terms
Acetamides, Animals, Cyclohexylamines, Disease Models, Animal, Humans, Membrane Proteins, Gene Deletion, Mice, Knockout, Eukaryotic Initiation Factor-2B, Hearing Loss, Mice, Transcription Factor CHOP, Unfolded Protein Response

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