TMPRSS3 Hearing Loss Overview
Learn about the Transmembrane Serine Protease 3 (TMPRSS3) gene and its related hearing loss, cochlear implants, and DFNB8/10 variants.
Transmembrane Serine Protease 3 (TMPRSS3) is a gene that encodes a protein. This protein belongs to the Type II Transmembrane Serine Protease family. Serine proteases are involved in many biological processes, and when these malfunction it can lead to diseases and disorders.
TMPRSS3 is essential for sensory cell/hair cell survival in the ear's cochlea. Without it, cochlear and vestibular functions can be limited or none. To learn more about how the ear functions, visit babyhearing.org - How The Ear Works.
TMPRSS3 does not seem to be expressed in spiral ganglion neurons (SGN type 1) (Group of neuron cell bodies in the cochlea's inner and outer hair cells.) located in the bony core of the human cochlea or neuronal cell populations of human inner ear organoids or has any clinically relevant biological role in the auditory nerve (Tucker, et al. 2021)
Biallelic pathogenic variants of TMPRSS3 are the most common causative hearing loss gene in adults undergoing traditional and hybrid cochlear implantation. Additionally, TMPRSS3 Is the fifth most common gene causally associated with deafness in a study of congenital (present at birth) deafness (YS Chen, et al. 2022).
Hearing Loss & DFNB8/10
The TMPRSS3 gene specifically was identified by its association with both congenital (present at birth) and childhood onset autosomal recessive deafness (happens in childhood when parents each pass down a copy of that gene that caused deafness).
The gene is expressed in the fetal cochlea and other tissues, and is involved in the development and maintenance of the inner ear.
The pathogenic variants in TMPRSS3 at DFNB8 locus, typically cause a post lingual (after speech) high-frequency/sloping hearing loss, with slow deterioration of the remaining hearing. Initially pathogenic variants of TMPRSS3 at DFNB8 may be treated with a hearing aid until declining hearing calls for a cochlear implant with Electrical Acoustic Stimulation (EAS) or a traditional cochlear implant (more information on Cochlear Implants below). EAS combines a hearing aid and cochlear implant technology. This timeframe could be anywhere from a young child to an adult.
Whereas, the effect of the pathogenic variants in TMPRSS3 at DFNB10 locus is congenital and prelingual (before speech) profound hearing loss at birth. This mutation is often treated with a traditional cochlear implant around one year of age or before.
DFNB8 and DFNB10 loci represent two large studies that originally linked hearing loss to this region of the genome. Once the families were found to have variants in the same gene, the genome locus was merged to now be called DFNB8/10. See Hereditary Hearing Loss Homepage and Johns Hopkins University School of Medicine's OMIM.
Today, families that have TMPRSS3 hearing loss can be described as simply having hearing loss due to pathogenic variants in TMPRSS3 which can range in how they present but are not specific to DFNB8 or DFNB10.
There have been 87 previously reported TMPRSS3 variants associated with non-syndromic (not associated with other signs and symptoms) hearing loss in more than 20 ancestral groups worldwide (IS Moon, 2021).
Schematic of TMPRSS3 protein and pathogenic/likely pathogenic reported deafness causing variants
Frequent variants causing congenital or postlingual hearing loss denoted in blue and orange, respectively. The TMPRSS3 autocleavage site (arrowhead) at R216 is shown and hexagons indicate the conserved serine protease catalytic triad (H-D-S). TM, transmembrane domain; LDLa, low-density lipoprotein receptor domain; NPT, non-protein truncating; PT, protein truncating; SRCR, scavenger receptor cysteine-rich domain. The amino acid number for the start and end of protein domains are noted. p.Gly393fs11 is an approximation-based description of the variant in the study by Scott et al. (YS Chen, et al., 2022)
Cochlear implantation remains the gold-standard treatment in inherited severe-profound sensorineural hearing loss (SNHL). Cochlear Implants (CI) function by directly stimulating spiral ganglion neurons in the cochlea, permitting sound detection and speech recognition, which gets rid of the need for functioning inner ear organs like cochlear hair cells.
Older research indicates CI outcomes in individuals with TMPRSS3 hearing loss varies, with some individuals exhibiting good speech outcomes while other individuals exhibiting poor outcomes.
Recent research has seen the outcome following cochlear implantation in individuals with pathogenic variants of TMPRSS3 as excellent. Cochlear implantation is strongly recommended for hearing rehabilitation in these individuals (IS Moon, 2021). Individuals with TMPRSS3 hearing loss exhibit similar postoperative performance to other adult CI patients. The duration of hearing loss prior to CI likely contributes to poor performance. Individuals with poorer performance tended to have longer durations of hearing loss prior to CI (Tucker, et al. 2021; YS Chen, et al. 2022).
These outcomes are all also determined by the person's determination and ability to adapt to cochlear implants. Months and years of aural rehabilitation and speech therapy will help the person to be able to successfully use cochlear implants.
In research on younger populations with TMPRSS3 hearing loss, findings suggest contributing factors such as children implanted with cochlear implants at a young age having much greater success than those who are older and haven't heard well for years. Results indicate that a CI with electric acoustic stimulation (EAS) is an appropriate treatment for children with the TMPRSS3 genetic mutation (DFNB8) (Holder et al., 2021) (Usami S. I. et al., 2020). Bilateral cochlear implantation with hearing preservation is a viable option for managing hearing loss for pediatric patients with TMPRSS3 mutations (Peng ZE et al., 2023).
In a new study on childhood-onset bilateral sensorineural hearing loss, researchers explain how among the genes they studied, the highest speech perception test scores were related to MITF and TMPRSS3. In a listening test, individuals with TMPRSS3 hearing loss averaged mean test scores of 89% in quiet and 58% in noise, being one of the highest scores from the genes they looked at. The researchers concluded that, because of this, it is extremely important to get genetic testing for children with sensorineural hearing loss. Genetic testing can identify patients whose genotypes suggests they may be a good candidate for cochlear implants (Carlson et al., 2023).
There have been some differing thoughts in this field and more research is being developed daily.
If you have TMPRSS3 hearing loss, it is likely that your hearing can be improved with a cochlear implant. Talk with your physician/ENT or find a cochlear implant clinic using the link below!
Pathogenic variants in TMPRSS3 at DFNB8/10 Locus & Cochlear Implants
The pathogenic variants in TMPRSS3 at DFNB8 locus are often seen in people with sloping hearing loss. Over time, that once usable hearing will degrade. People often become eligible for a cochlear implant (CI) when this happens. Newer research shows that utilization of a CI earlier may provide valuable electrical stimulation that can slow cell death over a longer period.
The pathogenic variants in TMPRSS3 at DFNB10 locus are linked to congenital hearing loss, and people with these variants often have severe to profound hearing loss. They are likely to be immediate candidates for cochlear implants.
Families that have pathogenic variants in TMPRSS3 at DFNB8/10 locus have hearing loss due to many different pathogenic variants and can vary in how they present. See examples in the audiograms below.
If you have received a diagnoses of a pathogenic variant in the TMPRSS3 gene at DFNB8/10 locus from genetic testing, and are told you are not a candidate for a CI, you should get a second opinion from another center.