Hepsin's Role in Profound Hearing Loss

 

Deafness occurs in approximately 1 in 1,000 children, with most cases of hearing impairment having a genetic cause. In 70% of childhood deafness cases, hearing loss is the only clinical manifestation. Because of the genetic components of these disorders, it is extremely difficult to study these issues. Most cases of genetic related hearing loss can only be examined post-mortem, so animal models are crucial for examining genetic causes of hearing impairment. In the work “Mice Deficient for the Type II Transmembrane Serine Protease, Tmprss1/hepsin, Exhibit Profound Hearing Loss” researchers analyze auditory abilities in mice without the Tmprss1 (hepsin) gene.

The Researchers conducted hearing evaluations in twenty knockout and heterozygous mice between seven and eight weeks of age. The click-evoked auditory brainstem response (ABR) was used to determine their ability to hear. The test delivers a brief auditory stimulus, if the stimulus is heard it will produce a brainwave response within ten milliseconds following the stimuli. During the test, the mice were anesthetized, and stimuli was delivered at various noise levels. During the evaluation, they found that the Tmprss1 knockout mice had no response to the 10-20 decibel attenuation (dBA) clicks. The knockout mice also had a sound pressure level threshold increase of 42dB compared to the mice with the Tmprss1 gene.

Following, cochlear histological analysis was conducted on the knockout and heterozygous mice. Tectorial membrane (TM) morphology in the heterozygous mice appeared normal, while the hepsin knockout mice had a large and deformed TM. The tectorial membrane in the knockouts had a reduced limbal attachment zone, along with large holes in its matrix. Reduced compaction of the soma and fibers of spiral ganglion neurons was also observed in the hepsin deficient mice. Further, the knockout mice had reduced levels of BK a-subunits. The researchers hypothesized that the lack of BK a-subunits may cause deficits in ion channel conductance within the organ of Corti, potentially worsening hearing. Additionally, it was discovered that the Tmprss1 knockout mice experienced a deficiency in thyroid hormones, which other studies have found to be essential for auditory system development.

Overall, the lack of the Tmprss1 gene in the knockout mice had catastrophic effects on their auditory system and thyroid function. Based on the results, it was suggested that type II serine proteases, like Tmprss1, may be crucial for normal development of the auditory system, as well as for proper functioning of the thyroid.

 

 

 

 

 

 

References

1. Guipponi M, Tan J, Cannon PZF, et al. Mice deficient for the type II transmembrane serine protease, TMPRSS1/hepsin, exhibit profound hearing loss. The American journal of pathology. August 2007. Accessed October 11, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934525/#:~:text=Defective%20proteolysis%20has%20been%20implicated,heterozygous%20and%20wild%2Dtype%20littermates.