As a scientist, it is easy to fall into the habit of looking at data with an end goal in mind. Strictly trying to prove or disprove a hypothesis, one may become selective in evaluating the outcomes of their work. When experimenting with something as complex as a genome, a researcher must be open to questioning the phenotypes that result from their manipulations, regardless of whether they immediately correspond to their predictions. In the case of Dr. Wei-Ming Yu and colleagues, their committed and observant perspective enabled them to look outside the bounds of their current research, and notice an unanticipated phenotype: partial cohort deafness. This observation allowed them to be the first to understand Hepsins’ role in the structural organization and development of the Tectorial Membrane, and ultimately, one's ability to hear.
Inspired by the observation that a knockout mouse cohort lacking TMPRSS1/hepsin (hepsin) displayed severe hearing loss, Dr. Yu questioned hepsin’s contribution to developing auditory complexes. A major structure responsible for the conversion of mechanical stimulation into electrical is the Tectorial Membrane (TM). This structure is primarily composed of both collagenous and noncollagenous glycoproteins. The noncollagenous glycoproteins alpha tectorin (TECTA) and beta tectorin (TECTB) were coexpressed with hepsin because they function as crosslinks between TM fibers. They are necessary components of the membrane's compact structure and if disrupted can lead to an inability to hear. Additionally, TECTA and TECTB contain Zona Pellucida (ZP) domains, which are essential to these proteins' polymerization; a process notably facilitated by hepsin: Dr. Yu’s protein of interest. Based on this information, one can theorize that if the expression of hepsin is disrupted or removed, the subsequent production of these glycoproteins would be deficient and lead to a structurally hindered tectorial membrane. To test this, Dr. Yu developed three transgenic mouse lines, all of which were crossed with a hepsin knockout cohort. The tectorial membrane in the initial hepsin knockout cohort was enlarged, perforated, and separated from the anchoring spiral limbus. The hearing threshold in this cohort was severely increased compared to the Wild-Type cohort, meaning their ability to register sound was greatly impaired. The first line, TgRS;KO, expresses a protease-dead mutant of human hepsin, its resulting phenotypic changes were non-functional in terms of restoring the structure of the TM, and its hearing threshold remained high. It is interesting to note that although this line was nonfunctional, it displayed the greatest rate of hepsin expression among the three lines. The second line,Tg5;KO, contained a lower expression of hepsin, and as such did not replenish the production of the tectorins or the structure of the TM. The final line, Tg68;KO, contained a higher expression of hepsin as well as an incomplete restoration of proteins TECTA and TECTB. This line displays a more structurally sound Tectorial Membrane that is partially attached to the spiral limbus. These structural changes may contribute to this line's decreased hearing threshold. Dr. Yu’s results suggest that the reintroduction of human hepsin could partially restore hearing, but that still leaves one to question: what else is necessary for complete auditory restoration?
A recent paper focused on genetic counseling against variants in a different transmembrane serine protease, TMPRSS3. This research assessed how cochlear implants assisted human participants who suffered from autosomal recessive non-syndromic hearing loss. These patients presented both congenital and late-onset hearing loss and this mutated variant resulted in restricted hearing at higher frequencies. This variant causes structural changes to the cochlear ear cells, which may be a key factor in the participants’ loss of hearing. By directly stimulating the auditory nerve and bypassing any damaged structures, the cochlear implants (CI) used in this study offered a positive impact on the patients. On average, the participants who received the CI counseling reported an increase in hearing.
Although there is a gap in the field regarding humans with diminished or non-existent TMPRSS1 expression, the idea that cochlear implants could bypass structural malformations suggests that individuals with partially attached Tectorial Membranes may benefit from this auditory therapy. However, this potential hearing restoration may only be applicable to individuals with partially attached TM. If it is determined at a pre-embryonic state that the offspring will present completely detached TM, early genetic intervention will likely be necessary, as proposed by Dr. Yu. These two therapies working in concert offer a foundation for future studies regarding restoring hearing to those deficient in hepsin/TMPRSS1.
Guipponi, M., Molina, F., Fasquelle, L., Nouvian, R., Salvetat, N., Scott, H. S., Puel, J. L., & Delprat, B. (2002). Tmprss3 loss of function impairs cochlear inner hair cell Kcnma1 channel membrane expression. Human Molecular Genetics, 22(7), 1289-1299. https://doi.org/10.1093/hmg/dds532
Moon, I. S., Grant, A. R., Sagi, V., Rehm, H. L., & Stankovic, K. M. (2021). TMPRSS3 Gene Variants With Implications for Auditory Treatment and Counseling. Frontiers in Genetics, 12, 780874. https://doi.org/10.3389/fgene.2021.780874
Yu, Wei-Ming. (2024). Critical role of hepsin/TMPRSS1 in hearing and tectorial membrane morphogenesis: insights from transgenic mouse models.
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