Researchers Identify ‘Essential’ Hearing Loss Gene

In a recent article, published in an October edition of the Journal of Clinical Investigation, [i] researchers at the University of California, San Francisco, examine their discovery of a gene, which plays an ‘essential’ role in the onset of noise-induced hearing loss:[ii]

‘We were able to go from observation to mechanism to treatment in one window of time, which was really exciting’.

The team of researchers, led by Professor of Neurology and Paediatrics, Elliott Sherr MD, was interested in the function of Tmtc4 (transmembrane and tetratricopeptide repeat 4) in brain development. At the beginning of their investigation, the Tmtc4 gene was deleted in mouse embryos.

One month after the mice were born, the researchers were surprised to discover that the mice without Tmtc4 were ‘almost completely deaf’. Congenital hearing loss was ruled out, as all test subjects had normal hearing function at birth.

Hearing loss is typically caused by damage to the sensory hair cells in the cochlea, which are responsible for detecting sound waves and transmitting auditory information to the brain. Hair cells cannot regenerate after they die.

In this latest study, deafness in mice was attributed to the deletion of Tmtc4. Dr Sherr’s group explained that Tmtc4 removal distorted the balance of calcium between the endoplasmic reticulum and the rest of the hair cell. 

Annotated diagram of a cochlear hair cell:


This calcium imbalance triggered an unfolded protein response (UPR) – a quality control system, whereby cells self-destruct to avoid producing faulty or dangerous proteins. Repeated ‘hair-cell suicide’ can cause hearing loss, ultimately leading to total deafness.

In further tests, the researchers exposed unaffected mice to loud aural stimuli and observed that hair cell death was triggered by the same UPR as the mice lacking the Tmtc4 gene. In this way, the researchers were able to deduce that the rapid hearing loss observed in Tmtc4-deficient mice was due to heightened sensitivity to normal sounds:

‘No one had shown that noise-induced hearing loss involved the unfolded protein response.

The UPR was therefore highlighted as a target for potential NIHL therapy.

In 2013, Peter Walter Ph.D, Professor of Biochemistry and Biophysics, identified a drug, called ISRIB (for Integrated Stress Response Inhibitor), which inhibits the UPR and prevents hair cells from self-destructing. The drug was able to reverse memory failure caused by traumatic brain injury and eliminate aggressive prostate cancer cells.

The researchers in the latest study found that mice, administered with ISRIB before they were exposed to loud noises, prevented hair cell damage and noise-induced hearing loss. Further research will concentrate on preventing age-related hearing loss.

A similar drug to ISRIB could one day be taken by employees in noisy workplaces as a form of hearing-protection.


[i] Jiang Li et al. Deletion of Tmtc4 activates the unfolded protein response and causes postnatal hearing loss, Journal of Clinical Investigation (2018). DOI: 10.1172/JCI97498

[ii] Jason Alvarez, ‘Gene plays critical role in noise-induced deafness’ (19 October 2018 Medical Xpress) <> accessed 30 October 2018.