HGNC Approved Gene Symbol: TMPRSS3
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38): 21:42,371,890-42,396,052 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Deafness, autosomal recessive 8/10 | 601072 | Autosomal recessive | 3 |
TMPRSS3 is a type II transmembrane serine protease, structurally defined by an N-terminal transmembrane domain; a low density lipoprotein (LDL) receptor A domain, which binds calcium and LDL; a scavenger receptor cysteine-rich domain involved in protein-protein interactions; and a C-terminal serine protease domain from the S1 family of the SA clan of serine-type peptidases, for which the prototype is chymotrypsin (see 118888). Mutations in the TMPRSS3 gene cause autosomal recessive nonsyndromic deafness (DFNB8/10; 601072), indicating a critical role for TMPRSS3 in the auditory system (summary by Fasquelle et al., 2011).
Scott et al. (2001) identified a novel gene within the DFNB8/DFNB10 (601072) critical region on 21q, which they designated TMPRSS3. Scott et al. (2001) detected 4 alternative transcripts encoding putative polypeptides of 454, 327, 327, and 344 amino acids. Northern blot analysis detected weak expression of 2.4- and 1.4-kb transcripts. RT-PCR revealed that the gene is expressed in many tissues, including fetal cochlea.
Guipponi et al. (2002) cloned the mouse ortholog of TMPRSS3, which is structurally similar to the human gene and encodes a polypeptide with 88% identity to the human protein. Murine Tmprss3 is expressed in the spiral ganglion, the cells supporting the organ of Corti, and the stria vascularis, as well as in thymus, stomach, testis, and embryos at embryonic day 19 (E19). Transient expression of TMPRSS3 showed a primary localization in the endoplasmic reticulum (ER).
Fasquelle et al. (2011) identified a splice variant of mouse Tmprss3, which they called Tmprss3f, that includes an upstream exon and encodes a deduced 476-amino acid protein. Database analysis revealed human TMPRSS3F, which encodes a deduced 478-amino acid protein that shares 89% identity with mouse Tmprss3f and has an N-terminal extension compared with the 454-amino acid human TMPRSS3A isoform. RT-PCR of young mice revealed high Tmprss3a expression in liver, cochlea, brain, cerebellum, spleen, lung, and muscle, with lower expression in retina, kidney, and heart. High Tmprss3f expression was detected only in cochlea, with faint expression in cerebellum, spleen, and muscle. Tmprss3a and Tmprss3f colocalized with a marker of the ER in transfected HeLa cells.
The epithelial amiloride-sensitive sodium channel (ENaC), which is expressed in many sodium-reabsorbing tissues, including the inner ear, and is regulated by membrane-bound channel activating serine proteases, is a potential substrate of TMPRSS3. In a Xenopus oocyte expression system, Guipponi et al. (2002) observed that proteolytic processing of TMPRSS3 was associated with increased ENaC-mediated currents. In contrast, 6 TMPRSS3 missense mutants causing deafness failed to undergo proteolytic cleavage and activate ENaC. Guipponi et al. (2002) proposed that important signaling pathways in the inner ear may be controlled by proteolytic cleavage, including autocatalytic activation of TMPRSS3, and that ENaC could be a substrate of TMPRSS3 in the inner ear.
Scott et al. (2001) determined that the TMPRSS3 gene contains 13 exons spanning 24 kb.
Scott et al. (2001) identified the TMPRSS3 gene on chromosome 21q22.3.
Fasquelle et al. (2011) stated that the mouse Tmprss3 gene maps to chromosome 17.
Scott et al. (2001) identified mutations in the TMPRSS3 gene in autosomal recessive neurosensory deafness. In a Pakistani family with DFNB8, they identified a splice site mutation (605511.0002) in intron 4. In a Palestinian family with the form of deafness designated DFNB10, they identified a mutation (605511.0001) consisting of an 8-bp deletion and insertion of 18 complete beta-satellite repeat monomers, which are normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes. The mobile nature of repetitive sequences on the short arms of acrocentric chromosomes is well documented. Although chromosomal rearrangements involving beta-satellites had been described, this was the first description of beta-satellite insertion into an active gene resulting in a pathogenic state. This was also the first description of a protease involved in hearing loss.
Ben-Yosef et al. (2001) identified mutations in 4 families from Pakistan with congenital profound nonsyndromic sensorineural deafness in 159 families studied.
Lee et al. (2003) noted that pathogenic mutations resulting in nonsyndromic autosomal recessive deafness had been identified in the low density lipoprotein receptor class A (LDLRA) and the scavenger receptor cysteine-rich (SRCR) domains, as well as the serine protease domain. They showed that all 6 pathogenic missense mutations they tested disrupted the proteolytic activity of TMPRSS3, whereas 2 nonpathogenic polymorphisms did not affect the activity. Thus, disruption of proteolytic activity of TMPRSS3 is highly correlated with the pathogenesis of deafness.
In 2 deaf Turkish brothers born of consanguineous parents, Wattenhofer et al. (2005) identified homozygosity for a missense mutation (R216L; 605511.0005). Functional characterization in Xenopus oocytes revealed that the R216L mutant failed to undergo proteolytic cleavage and did not activate ENaC. Wattenhofer et al. (2005) concluded that precleavage of TMPRSS3 is mandatory for normal function.
Following a screen of ethyl-nitrosourea-induced mutations in mice, Fasquelle et al. (2011) developed a line of mice carrying a tyr260-to-ter (Y260X) mutation in the Tmprss3 gene. Auditory brainstem responses revealed that homozygous Tmprss3(Y260X) mutants exhibited severe deafness compared with wildtype and heterozygous Tmprss3(Y260X) mutants. Immunohistochemical analysis and electron microscopic studies revealed degeneration of inner and outer hair cells in the organ of Corti that became evident only in postnatal mice commensurate with onset of hearing in wildtype animals. After postnatal day 90, homozygous Tmprss3(Y260X) mutants also showed progressive loss of spiral ganglion neurons. The remaining spiral ganglion neurons exhibited retraction of the cell body, deformation of nuclei, and disorganization of myelin envelope. Homozygous Tmprss3(Y260X) mice displayed a mild vestibular syndrome that correlated with degeneration of sensory epithelia of the saccules, but not cristae or utricles, of the vestibular end organ. Fasquelle et al. (2011) concluded that TMPRSS3 plays an essential role in the functional maturation of cochlear hair cells and in the maintenance of saccular hair cells.
Using patch-clamp recordings of day-10 postnatal wildtype and Y260X mutant apical inner hair cells, Molina et al. (2013) found that only outward K+ currents were altered in Y260X mutant mice. Use of 2-dimensional gels, followed by mass spectrometric and bioinformatic analyses, functional studies, and immunohistochemistry showed that loss of the Tmprss3 protease domain led to decreased plasma membrane expression of the K+ channel Kcnma1 (600150), concomitant with downregulation of the Kcnma1-interacting protein Apoa1 (107680) in inner hair cells.
In a Palestinian family with autosomal recessive deafness-8 (DFNB8; 601072), also known as DFNB10, Scott et al. (2001) found that exon 11 of the TMPRSS3 gene contained a 1.7-kb product instead of the 476-bp product amplified from normal controls. Eight affected individuals were homozygous for this product; 13 obligate carriers had one copy. Sequence analysis showed a complex rearrangement with deletion of 8 bp and insertion of 18 complete beta-satellite repeat monomers.
In a Pakistani family with autosomal recessive deafness-8 (DFNB8; 601072), Scott et al. (2001) identified a G-to-A substitution at position -6 of the splice acceptor site of intron 4 in the TMPRSS3 gene. The change created an alternative splice acceptor site and the insertion of 4 bp between exons 4 and 5. Scott et al. (2001) suspected that in vivo the IVS4AS-6G-A mutation may allow limited normal splicing, and thus some normal TMPRSS3 protein, accounting for the phenotypic difference between the DFNB8 and DFNB10 families.
In individuals with congenital nonsyndromic autosomal recessive deafness (DFNB8; 601072) in a consanguineous Tunisian family, Masmoudi et al. (2001) found homozygosity for a G-to-C transversion in the TMPRSS3 gene, leading to a trp251-to-cys (W251C) missense mutation. Comparative protein modeling of the TMPRSS3 protease domain predicted that W251C may lead to a structural rearrangement affecting the active site his257.
In a consanguineous Tunisian family, Masmoudi et al. (2001) found that individuals with congenital nonsyndromic autosomal recessive deafness (DFNB8; 601072) were homozygous for a 1221C-T transition in the TMPRSS3 gene, leading to a pro404-to-leu (P404L) missense mutation. Comparative protein modeling of the TMPRSS3 protease domain predicted that P404L may alter the geometry of the active site loop and therefore affect the serine protease activity.
In affected members of a consanguineous Turkish family with childhood-onset neurosensory deafness, Wattenhofer et al. (2005) identified homozygosity for the P404L mutation in the TMPRSS3 gene. All affected members of this family were hearing until the age of 6 or 7 years, in contrast to the previously reported Tunisian family (Masmoudi et al., 2001). Haplotype analysis suggested a different origin for the mutation in the 2 families.
In 2 Turkish brothers with nonsyndromic deafness (DFNB8; 601072), born of consanguineous parents, Wattenhofer et al. (2005) identified homozygosity for a 647G-T transversion in the TMPRSS3 gene, resulting in an arg216-to-leu (R216L) substitution. Functional characterization in Xenopus oocytes revealed that the R216L mutant failed to undergo proteolytic cleavage and did not activate ENaC. The elder brother's deafness, the first case to occur in the family, was discovered at age 1.5 years due to speech delay; deafness in the younger brother was diagnosed at birth. The parents were heterozygous for the mutation, and a hearing sister was homozygous for the normal allele.
In a Greek patient with prelingual nonsyndromic sensorineural deafness (DFNB8; 601072), Wattenhofer et al. (2002) identified compound heterozygosity for 2 mutations in exon 4 of the TMPRSS3 gene: a 1-bp deletion (207delC) resulting in a frameshift and a 308A-G transition resulting in an asp103-to-gly (D103G) substitution (605511.0007) in the LDLRA domain.
In a Spanish patient with prelingual nonsyndromic sensorineural deafness, Wattenhofer et al. (2002) identified homozygosity for the 207delC mutation.
For discussion of the asp103-to-gly (D103G) mutation in the TMPRSS3 gene that was found in compound heterozygous state in a patient with prelingual nonsyndromic sensorineural deafness (DFNB8; 601072) by Wattenhofer et al. (2002), see 605511.0006.
Ben-Yosef, T., Wattenhofer, M., Riazuddin, S., Ahmed, Z. M., Scott, H. S., Kudoh, J., Shibuya, K., Antonarakis, S. E., Bonne-Tamir, B., Radhakrishna, U., Naz, S., Ahmed, Z., Riazuddin, S., Pandya, A., Nance, W. E., Wilcox, E. R., Friedman, T. B., Morell, R. J. Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. (Letter) J. Med. Genet. 38: 396-400, 2001. [PubMed: 11424922] [Full Text: https://doi.org/10.1136/jmg.38.6.396]
Fasquelle, L., Scott, H. S., Lenoir, M., Wang, J., Rebillard, G., Goboyard, S., Venteo, S., Francois, F., Mausset-Bonnefont, A.-L., Antonarakis, S. E., Neidhart, E., Chabbert, C., Puel, J.-L., Guipponi, M., Delprat, B. Tmprss3, a transmembrane serine protease deficient in human DFNB8/10 deafness, is critical for cochlear hair cell survival at the onset of hearing. J. Biol. Chem. 286: 17383-17397, 2011. [PubMed: 21454591] [Full Text: https://doi.org/10.1074/jbc.M110.190652]
Guipponi, M., Vuagniaux, G., Wattenhofer, M., Shibuya, K., Vazquez, M., Dougherty, L., Scamuffa, N., Guida, E., Okui, M., Rossier, C., Hancock, M., Buchet, K., Reymond, A., Hummler, E., Marzella, P. L., Kudoh, J., Shimizu, N., Scott, H. S., Antonarakis, S. E., Rossier, B. C. The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum. Molec. Genet. 11: 2829-2836, 2002. [PubMed: 12393794] [Full Text: https://doi.org/10.1093/hmg/11.23.2829]
Lee, Y. J., Park, D., Kim, S. Y., Park, W. J. Pathogenic mutations but not polymorphisms in congenital and childhood onset autosomal recessive deafness disrupt the proteolytic activity of TMPRSS3. J. Med. Genet. 40: 629-631, 2003. [PubMed: 12920079] [Full Text: https://doi.org/10.1136/jmg.40.8.629]
Masmoudi, S., Antonarakis, S. E., Schwede, T., Ghorbel, A. M., Gratri, M., Pappasavas, M.-P., Drira, M., Elgaied-Boulila, A., Wattenhofer, M., Rossier, C., Scott, H. S., Ayadi, H., Guipponi, M. Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with nonsyndromic autosomal recessive deafness. Hum. Mutat. 18: 101-108, 2001. [PubMed: 11462234] [Full Text: https://doi.org/10.1002/humu.1159]
Molina, L., Fasquelle, L., Nouvian, R., Salvetat, N., Scott, H. S., Guipponi, M., Molina, F., Puel, J.-L., Delprat, B. Tmprss3 loss of function impairs cochlear inner hair cell Kcnma1 channel membrane expression. Hum. Molec. Genet. 22: 1289-1299, 2013. [PubMed: 23255163] [Full Text: https://doi.org/10.1093/hmg/dds532]
Scott, H. S., Kudoh, J., Wattenhofer, M., Shibuya, K., Berry, A., Chrast, R., Guipponi, M., Wang, J., Kawasaki, K., Asakawa, S., Minoshima, S., Younus, F., and 10 others. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nature Genet. 27: 59-63, 2001. [PubMed: 11137999] [Full Text: https://doi.org/10.1038/83768]
Wattenhofer, M., Di Iorio, M. V., Rabionet, R., Dougherty, L., Pampanos, A., Schwede, T., Montserrat-Sentis, B., Arbones, M. L., Iliades, T., Pasquadibisceglie, A., D'Amelio, M., Alwan, S., Rossier, C., Dahl, H.-H. M., Petersen, M. B., Estivill, X., Gasparini, P., Scott, H. S., Antonarakis, S. E. Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. J. Molec. Med. 80: 124-131, 2002. [PubMed: 11907649] [Full Text: https://doi.org/10.1007/s00109-001-0310-6]
Wattenhofer, M., Sahin-Calapoglu, N., Andreasen, D., Kalay, E., Caylan, R., Braillard, B., Fowler-Jaeger, N., Reymond, A., Rossier, B. C., Karaguzel, A., Antonarakis, S. E. A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein. Hum. Genet. 117: 528-535, 2005. [PubMed: 16021470] [Full Text: https://doi.org/10.1007/s00439-005-1332-x]