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Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss
- Source :
- The Journal of clinical investigation, vol 128, iss 11
- Publication Year :
- 2018
- Publisher :
- American Society for Clinical Investigation, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Hearing loss
Knockout
Immunology
Otology
Medical and Health Sciences
Mice
03 medical and health sciences
Acetamides
Genetics
otorhinolaryngologic diseases
medicine
Animals
Humans
2.1 Biological and endogenous factors
Integrated stress response
Aetiology
Hearing Loss
Calcium signaling
Mice, Knockout
Cyclohexylamines
biology
Animal
Prevention
Endoplasmic reticulum
Neurosciences
Membrane Proteins
Ear
Cell Biology
General Medicine
Cell stress
ISRIB
Cell biology
Disease Models, Animal
Eukaryotic Initiation Factor-2B
Tetratricopeptide
030104 developmental biology
Disease Models
eIF2B
Unfolded Protein Response
Unfolded protein response
biology.protein
medicine.symptom
Gene Deletion
Transcription Factor CHOP
Research Article
Genetic diseases
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 128
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....73111e4f543aa7814ff0c1a3283fc1b1