Skip to main content
SpringerLink
Log in

A novel mutation of TMPRSS3 related to milder auditory phenotype in Korean postlingual deafness: a possible future implication for a personalized auditory rehabilitation

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Appropriate customized auditory rehabilitation for hearing impaired subjects requires prediction of residual hearing and progression of hearing loss. Mutations in TMPRSS3 encoding a transmembrane serine protease were reported to be associated with two different autosomal recessive nonsyndromic hearing loss (arNSHL) phenotypes, DFNB8 and DFNB10, in terms of residual hearing that may mandate different rehabilitation. We aimed to reveal the genetic contribution of TMPRSS3 mutations among Korean populations and to correlate the clinical phenotype with TMPRSS3 genotypes. Fifty families that segregated arNSHL and have visited our clinic recently for 2 years were recruited for TMPRSS3 screening. Novel TMPRSS3 variants detected in our cohort were modeled using a predicted three-dimensional (3D) structure of the serine protease domain. The prevalence reached up to 11.2 % (3/27) among subjects with either prelingual hearing loss but retaining some degree of language development or with postlingual ski-slope hearing loss. We also found that a p.A306T allele is a founder allele in this population. Based upon the 3D modeling, we were able to correlate significant retention of residual low-frequency hearing and slower progression of its loss to this novel variant p.T248M that was predicted to have milder pathogenicity. A yeast-based protease assay confirmed a mild pathogenic potential of the p.T248M variant and a tight correlation between the protease activity and the residual hearing. Preservation of this low-frequency hearing should be of utmost importance when considering auditory rehabilitation. Our results significantly narrow down the candidate population for TMPRSS3 sequencing for more efficient genetic diagnosis. More importantly, genotype–phenotype correlation of this gene observed in our cohort suggests that TMPRSS3 can be an appropriate candidate for personalized and customized auditory rehabilitation.

Key message

  • The prevalence of TMPRSS3 mutations among Korean postlingual hearing loss is 8.3 %.

  • The p.A306T variant of TMPRSS3 is the common founder allele in Koreans.

  • A novel variant, p.T248M of TMPRSS3, was predicted to have milder pathogenicity.

  • There was a genotype–phenotype correlation of this gene in Koreans.

  • Our data support implication of this gene for personalized rehabilitation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Kalatzis V, Petit C (1998) The fundamental and medical impacts of recent progress in research on hereditary hearing loss. Hum Mol Genet 7:1589–1597

    Article  CAS  PubMed  Google Scholar 

  2. Petersen MB, Willems PJ (2006) Non-syndromic, autosomal-recessive deafness. Clin Genet 69:371–392

    Article  CAS  PubMed  Google Scholar 

  3. Veske A, Oehlmann R, Younus F, Mohyuddin A, Muller-Myhsok B, Mehdi SQ, Gal A (1996) Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan. Hum Mol Genet 5:165–168

    Article  CAS  PubMed  Google Scholar 

  4. Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J, Kawasaki K, Asakawa S et al (2001) Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet 27:59–63

    CAS  PubMed  Google Scholar 

  5. Bonne-Tamir B, DeStefano AL, Briggs CE, Adair R, Franklyn B, Weiss S, Korostishevsky M, Frydman M, Baldwin CT, Farrer LA (1996) Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3. Am J Hum Genet 58:1254–1259

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Weegerink NJ, Schraders M, Oostrik J, Huygen PL, Strom TM, Granneman S, Pennings RJ, Venselaar H, Hoefsloot LH, Elting M et al (2011) Genotype–phenotype correlation in DFNB8/10 families with TMPRSS3 mutations. J Assoc Res Otolaryngol 12:753–766

    Article  PubMed Central  PubMed  Google Scholar 

  7. Lee YJ, Park D, Kim SY, Park WJ (2003) 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Guipponi M, Toh MY, Tan J, Park D, Hanson K, Ballana E, Kwong D, Cannon PZ, Wu Q, Gout A et al (2008) An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss. Hum Mutat 29:130–141

    Article  CAS  PubMed  Google Scholar 

  9. Hutchin T, Coy NN, Conlon H, Telford E, Bromelow K, Blaydon D, Taylor G, Coghill E, Brown S, Trembath R et al (2005) Assessment of the genetic causes of recessive childhood non-syndromic deafness in the UK—implications for genetic testing. Clin Genet 68:506–512

    Article  CAS  PubMed  Google Scholar 

  10. Wattenhofer M, Di Iorio MV, Rabionet R, Dougherty L, Pampanos A, Schwede T, Montserrat-Sentis B, Arbones ML, Iliades T, Pasquadibisceglie A et al (2002) Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. J Mol Med (Berl) 80:124–131

    Article  CAS  Google Scholar 

  11. Elbracht M, Senderek J, Eggermann T, Thurmer C, Park J, Westhofen M, Zerres K (2007) Autosomal recessive postlingual hearing loss (DFNB8): compound heterozygosity for two novel TMPRSS3 mutations in German siblings. J Med Genet 44:e81

    Article  PubMed Central  PubMed  Google Scholar 

  12. Meyer TA, Svirsky MA, Kirk KI, Miyamoto RT (1998) Improvements in speech perception by children with profound prelingual hearing loss: effects of device, communication mode, and chronological age. J Speech Lang Hear Res JSLHR 41:846–858

    CAS  Google Scholar 

  13. King KA, Choi BY, Zalewski C, Madeo AC, Manichaikul A, Pryor SP, Ferruggiaro A, Eisenman D, Kim HJ, Niparko J et al (2010) SLC26A4 genotype, but not cochlear radiologic structure, is correlated with hearing loss in ears with an enlarged vestibular aqueduct. Laryngoscope 120:384–389

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Ben-Yosef T, Wattenhofer M, Riazuddin S, Ahmed ZM, Scott HS, Kudoh J, Shibuya K, Antonarakis SE, Bonne-Tamir B, Radhakrishna U et al (2001) Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. J Med Genet 38:396–400

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Kim SY, Park G, Han KH, Kim A, Koo JW, Chang SO, Oh SH, Park WY, Choi BY (2013) Prevalence of p.V37I variant of GJB2 in mild or moderate hearing loss in a pediatric population and the interpretation of its pathogenicity. PloS One 8:e61592

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Kim SY, Park D, Oh M, Sellamuthu S, Park WJ (2002) Detection of site-specific proteolysis in secretory pathways. Biochem Biophys Res Commun 296:419–424

    Article  CAS  PubMed  Google Scholar 

  17. Yan D, Park HJ, Ouyang XM, Pandya A, Doi K, Erdenetungalag R, Du LL, Matsushiro N, Nance WE, Griffith AJ et al (2003) Evidence of a founder effect for the 235delC mutation of GJB2 (connexin 26) in east Asians. Hum Genet 114:44–50

    Article  CAS  PubMed  Google Scholar 

  18. Park HJ, Shaukat S, Liu XZ, Hahn SH, Naz S, Ghosh M, Kim HN, Moon SK, Abe S, Tukamoto K et al (2003) Origins and frequencies of SLC26A4 (PDS) mutations in east and south Asians: global implications for the epidemiology of deafness. J Med Genet 40:242–248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Masmoudi S, Antonarakis SE, Schwede T, Ghorbel AM, Gratri M, Pappasavas MP, Drira M, Elgaied-Boulila A, Wattenhofer M, Rossier C et al (2001) Novel missense mutations of TMPRSS3 in two consanguineous Tunisian families with non-syndromic autosomal recessive deafness. Hum Mutat 18:101–108

    Article  CAS  PubMed  Google Scholar 

  20. Wattenhofer M, Sahin-Calapoglu N, Andreasen D, Kalay E, Caylan R, Braillard B, Fowler-Jaeger N, Reymond A, Rossier BC, Karaguzel A et al (2005) A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein. Hum Genet 117:528–535

    Article  CAS  PubMed  Google Scholar 

  21. Lee J, Baek JI, Choi JY, Kim UK, Lee SH, Lee KY (2013) Genetic analysis of TMPRSS3 gene in the Korean population with autosomal recessive nonsyndromic hearing loss. Gene 532:276–280

    Article  CAS  PubMed  Google Scholar 

  22. Fasquelle L, Scott HS, Lenoir M, Wang J, Rebillard G, Gaboyard S, Venteo S, Francois F, Mausset-Bonnefont AL, Antonarakis SE et al (2011) 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Otte J, Schunknecht HF, Kerr AG (1978) Ganglion cell populations in normal and pathological human cochleae. Implications for cochlear implantation. Laryngoscope 88:1231–1246

    Article  CAS  PubMed  Google Scholar 

  24. Eppsteiner RW, Shearer AE, Hildebrand MS, Deluca AP, Ji H, Dunn CC, Black-Ziegelbein EA, Casavant TL, Braun TA, Scheetz TE et al (2012) Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis. Hear Res 292:51–58

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Seoul National University Bundang Hospital research fund and SK Telecom (health connect) (06-2013-094 to B.Y. Choi) and also by the Korean Health Technology R&D project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (No. A111377 to B. Y. Choi). The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Disclosure

The authors declare no conflict of interests related to this study.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Ajou University School of Medicine, Suwon, South Korea

    Juyong Chung

  2. Department of Life Science, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea

    Sang Min Park & Woo Jin Park

  3. Department of Otorhinolaryngology—Head and Neck Surgery, Seoul National University College of Medicine, Seoul, South Korea

    Sun O Chang, Ah Reum Kim, Joo Hyun Park & Seung-Ha Oh

  4. Sensory Organ Research Institute, Seoul National University Medical Research Center, Seoul, South Korea

    Sun O Chang, Seung-Ha Oh & Byung Yoon Choi

  5. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea

    Taesu Chung, Kyoung Yeul Lee & Dongsup Kim

  6. Department of Cell and System Biology, University of Toronto, Toronto, Canada

    Veronica Kim

  7. Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea

    Woong-Yang Park

  8. Translational Genomics Laboratory, Samsung Institute, Samsung Medical Center, Seoul, South Korea

    Woong-Yang Park

  9. Department of Otolaryngology—Head and Neck Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707, South Korea

    Byung Yoon Choi

Authors
  1. Juyong Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Min Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sun O Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taesu Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyoung Yeul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ah Reum Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joo Hyun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Veronica Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Woong-Yang Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Seung-Ha Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dongsup Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Woo Jin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Byung Yoon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Byung Yoon Choi.

Additional information

Juyong Chung and Sang Min Park contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, J., Park, S.M., Chang, S.O. et al. A novel mutation of TMPRSS3 related to milder auditory phenotype in Korean postlingual deafness: a possible future implication for a personalized auditory rehabilitation. J Mol Med 92, 651–663 (2014). https://doi.org/10.1007/s00109-014-1128-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-014-1128-3

Keywords

Search

Navigation