Subscribe to RSS
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/s-0043-121595
Molecular Understanding of Hearing – How Does This Matter to the Hearing Impaired?
Article in several languages: deutsch | EnglishPublication History
Publication Date:
22 March 2018 (online)
![](https://www.thieme-connect.de/media/lro/2018S01/lookinside/thumbnails/4982274_10-1055-s-0043-121595_en-1.jpg)
Abstract
This review addresses the advances of our molecular understanding of hearing and how this benefits the hearing impaired. Classical biochemical methods usually fall short in contributing to the analysis of the molecular mechanisms of hearing e. g. in the cochlea, the auditory part of the inner ear, due to the scarcity of the cells of interest. Genetics, molecular cell biology, and physiology, on the other hand, have elucidated the intricate molecular and cellular mechanisms that bring about the outstanding performance of the auditory system. Many of those mechanisms are quite unique and specialized to serve the specific needs of hearing. Hence, their defects often spare other organs and lead to specific non-syndromic deafness. High throughput sequencing can reveal causes of sporadic deafness when combined with careful bioinformatics. Molecular approaches are also helpful for understanding more common forms of hearing impairment such as noise-induced hearing impairment. While molecular therapies are not yet clinically available, careful molecular genetic analysis helps to counsel the hearing impaired subjects.
-
Literatur
- 1 Petit C, Levilliers J, Hardelin JP. Molecular genetics of hearing loss. Annu Rev Genet 2001; 35: 589-646
- 2 Duman D, Tekin M. Autosomal recessive nonsyndromic deafness genes: a review. Front Biosci Landmark Ed 2012; 17: 2213-2236
- 3 Shearer AE, Smith RJH. Massively Parallel Sequencing for Genetic Diagnosis of Hearing Loss: The New Standard of Care. Otolaryngol--Head Neck Surg Off J Am Acad Otolaryngol-Head Neck Surg 2015; 153: 175-182
- 4 Atik T, Bademci G, Diaz-Horta O, Blanton SH, Tekin M. Whole-exome sequencing and its impact in hereditary hearing loss. Genet Res 2015; 97: e4
- 5 Richardson GP, de Monvel JB, Petit C. How the genetics of deafness illuminates auditory physiology. Annu Rev Physiol 2011; 73: 311-334
- 6 Vogl C, Panou I, Yamanbaeva G, Wichmann C, Mangosing SJ, Vilardi F, Indzhykulian AA, Pangršič T, Santarelli R, Rodriguez-Ballesteros M, Weber T, Jung S, Cardenas E, Wu X, Wojcik SM, Kwan KY, Del Castillo I, Schwappach B, Strenzke N, Corey DP, Lin S-Y, Moser T. Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing. EMBO J 2016
- 7 Moser T, Starr A. Auditory neuropathy — neural and synaptic mechanisms. Nat Rev Neurol 2016; 12: 135-149
- 8 Pauli-Magnus D, Hoch G, Strenzke N, Anderson S, Jentsch TJ, Moser T. Detection and differentiation of sensorineural hearing loss in mice using auditory steady-state responses and transient auditory brainstem responses. Neuroscience 2007; 149: 673-684
- 9 Strenzke N, Pauli-Magnus D, Meyer A, Brandt A, Maier H, Moser T. Update zur Physiologie und Pathophysiologie des Innenohrs. HNO 2008; 56: 27-36
- 10 Jung S, Maritzen T, Wichmann C, Jing Z, Neef A, Revelo NH, Al-Moyed H, Meese S, Wojcik SM, Panou I, Bulut H, Schu P, Ficner R, Reisinger E, Rizzoli SO, Neef J, Strenzke N, Haucke V, Moser T. Disruption of adaptor protein 2μ (AP-2μ) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing. EMBO J 2015; 34: 2686-2702
- 11 Askew C, Rochat C, Pan B, Asai Y, Ahmed H, Child E, Schneider BL, Aebischer P, Holt JR. Tmc gene therapy restores auditory function in deaf mice. Sci Transl Med 2015; 7: 295ra108
- 12 Landegger LD, Pan B, Askew C, Wassmer SJ, Gluck SD, Galvin A, Taylor R, Forge A, Stankovic KM, Holt JR, Vandenberghe LH. A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol 2017
- 13 Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, Jodelka FM, Hastings ML, Lentz JJ, Vandenberghe LH, Holt JR, Géléoc GS. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol 2017
- 14 Moser T. Gene therapy for deafness: How close are we?. Sci Transl Med 2015; 7: 295fs28
- 15 Brigande JV, Heller S. Quo vadis, hair cell regeneration?. Nat Neurosci 2009; 12: 679-685
- 16 Moser T. Optogenetic stimulation of the auditory pathway for research and future prosthetics. Curr Opin Neurobiol 2015; 34: 29-36
- 17 Identifier: NCT02132130. Safety, Tolerability and Efficacy for CGF166 in Patients With Bilateral Severe-to-profound Hearing Loss. Im Internet: ClinicalTrials.gov
- 18 Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF, Brough DE, Raphael Y. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 2005; 11: 271-276
- 19 Chen W, Jongkamonwiwat N, Abbas L, Eshtan SJ, Johnson SL, Kuhn S, Milo M, Thurlow JK, Andrews PW, Marcotti W, Moore HD, Rivolta MN. Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 2012; 490: 278-282
- 20 Koehler KR, Nie J, Longworth-Mills E, Liu X-P, Lee J, Holt JR, Hashino E. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol 2017; 35: 583-589
- 21 Liu X-P, Koehler KR, Mikosz AM, Hashino E, Holt JR. Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nat Commun 2016; 7: ncomms11508
- 22 Koehler KR, Mikosz AM, Molosh AI, Patel D, Hashino E. Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 2013; 500: 217-221
- 23 Wenzel GI, Balster S, Zhang K, Lim HH, Reich U, Massow O, Lubatschowski H, Ertmer W, Lenarz T, Reuter G. Green laser light activates the inner ear. J Biomed Opt 2009; 14: 044007
- 24 Schultz M, Baumhoff P, Maier H, Teudt IU, Krüger A, Lenarz T, Kral A. Nanosecond laser pulse stimulation of the inner ear – a wavelength study. Biomed Opt Express 2012; 3: 3332
- 25 Hernandez VH, Gehrt A, Reuter K, Jing Z, Jeschke M, Mendoza Schulz A, Hoch G, Bartels M, Vogt G, Garnham CW, Yawo H, Fukazawa Y, Augustine GJ, Bamberg E, Kügler S, Salditt T, de Hoz L, Strenzke N, Moser T. Optogenetic stimulation of the auditory pathway. J Clin Invest 2014; 124: 1114-1129
- 26 Goßler C, Bierbrauer C, Moser R, Kunzer M, Holc K, Pletschen W, Köhler K, Wagner J, Schwaerzle M, Ruther P, Paul O, Neef J, Keppeler D, Hoch G, Moser T, Schwarz UT. GaN-based micro-LED arrays on flexible substrates for optical cochlear implants. J Phys Appl Phys 2014; 47: 205401
- 27 Kubisch C, Schroeder BC, Friedrich T, Lütjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 1999; 96: 437-446
- 28 Kharkovets T, Dedek K, Maier H, Schweizer M, Khimich D, Nouvian R, Vardanyan V, Leuwer R, Moser T, Jentsch TJ. Mice with altered KCNQ4 K+ channels implicate sensory outer hair cells in human progressive deafness. EMBO J 2006; 25: 642-652
- 29 Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR. TMC1 and TMC2 Are Components of the Mechanotransduction Channel in Hair Cells of the Mammalian Inner Ear. Neuron 2013; 79: 504-515
- 30 Kawashima Y, Géléoc GSG, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest 2011. Im Internet: http://www.ncbi.nlm.nih.gov/pubmed/22105175
- 31 Kurima K, Ebrahim S, Pan B, Sedlacek M, Sengupta P, Millis BA, Cui R, Nakanishi H, Fujikawa T, Kawashima Y, Choi BY, Monahan K, Holt JR, Griffith AJ, Kachar B. TMC1 and TMC2 Localize at the Site of Mechanotransduction in Mammalian Inner Ear Hair Cell Stereocilia. Cell Rep 2015; 12: 1606-1617
- 32 Kazmierczak P, Müller U. Sensing sound: molecules that orchestrate mechanotransduction by hair cells. Trends Neurosci 2012; 35: 220-229
- 33 Oliver D. Prestin. In: The Senses: A Comprehensive Reference. New York: Academic Press; 2008: 309-317 Im Internet http://www.sciencedirect.com/science/article/B8SV0-4RD4KNB-1G/2/9074ccebb168117c7790bdc6ebd94932
- 34 Dallos P, Fakler B. Prestin, a new type of motor protein. Nat Rev Mol Cell Biol 2002; 3: 104-111
- 35 Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, Li F, Du LL, Welch KO, Petit C, Smith RJH, Webb BT, Yan D, Arnos KS, Corey D, Dallos P, Nance WE, Chen ZY. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol Genet 2003; 12: 1155-1162
- 36 Ryan A, Dallos P. Effect of absence of cochlear outer hair cells on behavioural auditory threshold. Nature 1975; 253: 44-46
- 37 Fettiplace R, Hackney CM. The sensory and motor roles of auditory hair cells. Nat Rev Neurosci 2006; 7: 19-29
- 38 Pangršič T, Reisinger E, Moser T. Otoferlin: a multi-C2 domain protein essential for hearing. Trends Neurosci 2012; 35: 671-680
- 39 Safieddine S, El-Amraoui A, Petit C. The auditory hair cell ribbon synapse: from assembly to function. Annu Rev Neurosci 2012; 35: 509-528
- 40 Moser T, Vogl C. New insights into cochlear sound encoding. F1000Research 2016; 5: 2081
- 41 Moser T, Predoehl F, Starr A. Review of hair cell synapse defects in sensorineural hearing impairment. Otol Neurotol Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol 2013; 34: 995-1004
- 42 Moser T, Strenzke N, Meyer A, Lesinski-Schiedat A, Lenarz T, Beutner D, Foerst A, Lang-Roth R, Wedel H, Walger M, Gross M, Keilmann A, Limberger A, Steffens T, Strutz J. Diagnostik und Therapie der auditorischen Synaptopathie/Neuropathie. HNO 2006; 54: 833-841
- 43 Akil O, Seal RP, Burke K, Wang C, Alemi A, During M, Edwards RH, Lustig LR. Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally Mediated Gene Therapy. Neuron 2012; 75: 283-293
- 44 Rance G, Starr A. Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy. Brain J Neurol 2015; 138: 3141-3158
- 45 Shearer AE, Eppsteiner RW, Frees K, Tejani V, Sloan-Heggen CM, Brown C, Abbas P, Dunn C, Hansen MR, Gantz BJ, Smith RJH. Genetic Variants in the Peripheral Auditory System Significantly Affect Adult Cochlear Implant Performance. Hear Res 2017; 348: 138-142
- 46 Liberman MC. Noise-induced and age-related hearing loss: new perspectives and potential therapies. F1000Research 2017; 6: 927
- 47 Kujawa SG, Liberman MC. Synaptopathy in the noise-exposed and aging cochlea: Primary neural degeneration in acquired sensorineural hearing loss. Hear Res 2015
- 48 Kujawa SG, Liberman MC. Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. J Neurosci 2009; 29: 14077
- 49 Khimich D, Nouvian R, Pujol R, Tom Dieck S, Egner A, Gundelfinger ED, Moser T. Hair cell synaptic ribbons are essential for synchronous auditory signalling. Nature 2005; 434: 889-894
- 50 Hübner CA, Jentsch TJ. Ion channel diseases. Hum Mol Genet 2002; 11: 2435-2445