ArticleThe Journal of clinical investigation2018
Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 65 citations in OpenAlex.
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- O-Mannose Glycosylations Influence E-Cadherin Functional Interactions.Molecular & cellular proteomics : MCP · 2026Article
- Heat-shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss.bioRxiv : the preprint server for biology · 2025Article
- Downregulation of TMTC4 expression is associated with improved prognosis in osteosarcoma.The Journal of international medical research · 2025Article
- Ototoxic impacts of adipose-derived extracts on a murine auditory cell line: molecular insights from proteomic analyses.International journal of obesity (2005) · 2025Article
- A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response.The Journal of clinical investigation · 2025Article
- Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome.The Journal of clinical investigation · 2025Article
- Maximizing ISRIB Potential Requires Addressing Specificity, Long-term Safety, and Disease-specific Considerations.Current medicinal chemistry · 2025Review
- Noise induces Ca2+ signaling waves and Chop/S-Xbp1 expression in the hearing cochlea.JCI insight · 2024Article
- The single-cell transcriptomic landscape of the topological differences in mammalian auditory receptors.Science China. Life sciences · 2024Article
- Polymer scaffolds delineate healthy from diseased states at sites distal from the pancreas in two models of type 1 diabetes.Biotechnology and bioengineering · 2024Article
- Prognostic value ofHeliyon · 2024Article
- Modulating the unfolded protein response with ISRIB mitigates cisplatin ototoxicity.Scientific reports · 2024Article
- Global View of Domain-Specific O-Linked Mannose Glycosylation in Glycoengineered Cells.Molecular & cellular proteomics : MCP · 2024Article
- Article
- Insights into the molecular underlying mechanisms and therapeutic potential of endoplasmic reticulum stress in sensorineural hearing loss.Frontiers in molecular neuroscience · 2024Review
- Protein O-mannosylation: one sugar, several pathways, many functions.Glycobiology · 2023Review
- TMTC4 is a hair cell-specific human deafness gene.JCI insight · 2023Article
- miR-3200 accelerates the growth of liver cancer cells by enhancing Rab7A.Non-coding RNA research · 2023Article
- Functional unknomics: Systematic screening of conserved genes of unknown function.PLoS biology · 2023Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.