THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis

Autoři: Luping Zhang aff001;  Yu Gao aff001;  Ru Zhang aff002;  Feifei Sun aff001;  Cheng Cheng aff003;  Fuping Qian aff001;  Xuchu Duan aff001;  Guanyun Wei aff001;  Cheng Sun aff001;  Xiuhong Pang aff004;  Penghui Chen aff005;  Renjie Chai aff001;  Tao Yang aff005;  Hao Wu aff005;  Dong Liu aff001
Působiště autorů: Department of Otolaryngology-Head and Neck Surgery, Affiliated Hospital, School of Life Science, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China aff001;  Shanghai East Hospital, Department of Otorhinolaryngology Shanghai, Shanghai, China aff002;  Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing, China aff003;  Department of Otorhinolaryngology-Head and Neck Surgery, Taizhou People’s Hospital, Fifth Affiliated Hospital, Nantong University, Taizhou, China aff004;  Department of Otorhinolaryngology-Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China aff005;  Ear Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China aff006;  Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China aff007
Vyšlo v časopise: THOC1 deficiency leads to late-onset nonsyndromic hearing loss through p53-mediated hair cell apoptosis. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008953
Kategorie: Research Article


Apoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large family with autosomal dominant inheritance. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The thoc1 knockout (thoc1 mutant) zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the c.547C>G mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin-α significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.

Klíčová slova:

Apoptosis – Confocal microscopy – DAPI staining – Deafness – Fluorescence imaging – Linkage analysis – Messenger RNA – Zebrafish


1. Gates GA, Mills JH. Presbycusis. Lancet. 2005;366(9491):1111–20. doi: 10.1016/S0140-6736(05)67423-5 16182900.

2. Hwang JH, Chen JC, Hsu CJ, Yang WS, Liu TC. Plasma reactive oxygen species levels are correlated with severity of age-related hearing impairment in humans. Neurobiol Aging. 2012;33(9):1920–6. doi: 10.1016/j.neurobiolaging.2011.10.012 22133279.

3. Jiang H, Talaska AE, Schacht J, Sha SH. Oxidative imbalance in the aging inner ear. Neurobiol Aging. 2007;28(10):1605–12. doi: 10.1016/j.neurobiolaging.2006.06.025 16920227; PubMed Central PMCID: PMC2453750.

4. Sergeyenko Y, Lall K, Liberman MC, Kujawa SG. Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline. J Neurosci. 2013;33(34):13686–94. doi: 10.1523/JNEUROSCI.1783-13.2013 23966690; PubMed Central PMCID: PMC3755715.

5. Viana LM, O'Malley JT, Burgess BJ, Jones DD, Oliveira CA, Santos F, et al. Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue. Hear Res. 2015;327:78–88. doi: 10.1016/j.heares.2015.04.014 26002688; PubMed Central PMCID: PMC4554812.

6. Kwan T, White PM, Segil N. Development and regeneration of the inner ear. Ann N Y Acad Sci. 2009;1170:28–33. doi: 10.1111/j.1749-6632.2009.04484.x 19686102.

7. Yamasoba T, Lin FR, Someya S, Kashio A, Sakamoto T, Kondo K. Current concepts in age-related hearing loss: epidemiology and mechanistic pathways. Hear Res. 2013;303:30–8. doi: 10.1016/j.heares.2013.01.021 23422312; PubMed Central PMCID: PMC3723756.

8. Sha SH, Chen FQ, Schacht J. Activation of cell death pathways in the inner ear of the aging CBA/J mouse. Hear Res. 2009;254(1–2):92–9. doi: 10.1016/j.heares.2009.04.019 19422898; PubMed Central PMCID: PMC2749985.

9. Someya S, Xu J, Kondo K, Ding D, Salvi RJ, Yamasoba T, et al. Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis. Proc Natl Acad Sci U S A. 2009;106(46):19432–7. doi: 10.1073/pnas.0908786106 19901338; PubMed Central PMCID: PMC2780799.

10. Fransen E, Bonneux S, Corneveaux JJ, Schrauwen I, Di Berardino F, White CH, et al. Genome-wide association analysis demonstrates the highly polygenic character of age-related hearing impairment. Eur J Hum Genet. 2015;23(1):110–5. doi: 10.1038/ejhg.2014.56 24939585; PubMed Central PMCID: PMC4266741.

11. Friedman RA, Van Laer L, Huentelman MJ, Sheth SS, Van Eyken E, Corneveaux JJ, et al. GRM7 variants confer susceptibility to age-related hearing impairment. Hum Mol Genet. 2009;18(4):785–96. doi: 10.1093/hmg/ddn402 19047183; PubMed Central PMCID: PMC2638831.

12. Van Laer L, Huyghe JR, Hannula S, Van Eyken E, Stephan DA, Maki-Torkko E, et al. A genome-wide association study for age-related hearing impairment in the Saami. Eur J Hum Genet. 2010;18(6):685–93. doi: 10.1038/ejhg.2009.234 20068591; PubMed Central PMCID: PMC2987344.

13. Dror AA, Avraham KB. Hearing impairment: a panoply of genes and functions. Neuron. 2010;68(2):293–308. doi: 10.1016/j.neuron.2010.10.011 20955936.

14. Cheng J, Zhu Y, He S, Lu Y, Chen J, Han B, et al. Functional mutation of SMAC/DIABLO, encoding a mitochondrial proapoptotic protein, causes human progressive hearing loss DFNA64. Am J Hum Genet. 2011;89(1):56–66. doi: 10.1016/j.ajhg.2011.05.027 21722859; PubMed Central PMCID: PMC3135809.

15. Walsh T, Pierce SB, Lenz DR, Brownstein Z, Dagan-Rosenfeld O, Shahin H, et al. Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51. Am J Hum Genet. 2010;87(1):101–9. doi: 10.1016/j.ajhg.2010.05.011 20602916; PubMed Central PMCID: PMC2896780.

16. Li Y, Wang X, Zhang X, Goodrich DW. Human hHpr1/p84/Thoc1 regulates transcriptional elongation and physically links RNA polymerase II and RNA processing factors. Mol Cell Biol. 2005;25(10):4023–33. doi: 10.1128/MCB.25.10.4023-4033.2005 15870275; PubMed Central PMCID: PMC1087710.

17. Heath CG, Viphakone N, Wilson SA. The role of TREX in gene expression and disease. Biochem J. 2016;473(19):2911–35. doi: 10.1042/BCJ20160010 27679854; PubMed Central PMCID: PMC5095910.

18. Wang X, Chinnam M, Wang J, Wang Y, Zhang X, Marcon E, et al. Thoc1 deficiency compromises gene expression necessary for normal testis development in the mouse. Mol Cell Biol. 2009;29(10):2794–803. doi: 10.1128/MCB.01633-08 19307311; PubMed Central PMCID: PMC2682050.

19. Wang X, Li Y, Zhang X, Goodrich DW. An allelic series for studying the mouse Thoc1 gene. Genesis. 2007;45(1):32–7. doi: 10.1002/dvg.20262 17211872; PubMed Central PMCID: PMC2799240.

20. Xiao T, Roeser T, Staub W, Baier H. A GFP-based genetic screen reveals mutations that disrupt the architecture of the zebrafish retinotectal projection. Development. 2005;132(13):2955–67. doi: 10.1242/dev.01861 15930106.

21. He Y, Lu X, Qian F, Liu D, Chai R, Li H. Insm1a Is Required for Zebrafish Posterior Lateral Line Development. Frontiers in molecular neuroscience. 2017;10:241. doi: 10.3389/fnmol.2017.00241 28824372; PubMed Central PMCID: PMC5539400.

22. Gorczyca W, Traganos F, Jesionowska H, Darzynkiewicz Z. Presence of DNA strand breaks and increased sensitivity of DNA in situ to denaturation in abnormal human sperm cells: analogy to apoptosis of somatic cells. Exp Cell Res. 1993;207(1):202–5. Epub 1993/07/01. doi: 10.1006/excr.1993.1182 8391465.

23. Lozano GM, Bejarano I, Espino J, Gonzalez D, Ortiz A, Garcia JF, et al. Relationship between caspase activity and apoptotic markers in human sperm in response to hydrogen peroxide and progesterone. J Reprod Dev. 2009;55(6):615–21. Epub 2009/09/08. doi: 10.1262/jrd.20250 19734695.

24. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30. Epub 1999/12/11. doi: 10.1093/nar/28.1.27 10592173; PubMed Central PMCID: PMC102409.

25. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis—the p53 network. J Cell Sci. 2003;116(Pt 20):4077–85. Epub 2003/09/16. doi: 10.1242/jcs.00739 12972501.

26. Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB. Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells. Cell Death Differ. 2000;7(1):102–11. Epub 2000/03/14. doi: 10.1038/sj.cdd.4400597 10713725.

27. Porter AG, Janicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6(2):99–104. Epub 1999/04/14. doi: 10.1038/sj.cdd.4400476 10200555.

28. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479–89. Epub 1997/12/09. doi: 10.1016/s0092-8674(00)80434-1 9390557.

29. Chinnam M, Wang X, Zhang X, Goodrich DW. Evaluating Effects of Hypomorphic Thoc1 Alleles on Embryonic Development in Rb1 Null Mice. Mol Cell Biol. 2016;36(11):1621–7. doi: 10.1128/MCB.01003-15 27001308; PubMed Central PMCID: PMC4959316.

30. Dominguez-Sanchez MS, Saez C, Japon MA, Aguilera A, Luna R. Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers. BMC Cancer. 2011;11:77. doi: 10.1186/1471-2407-11-77 21329510; PubMed Central PMCID: PMC3050854.

31. Guo S, Hakimi MA, Baillat D, Chen X, Farber MJ, Klein-Szanto AJ, et al. Linking transcriptional elongation and messenger RNA export to metastatic breast cancers. Cancer Res. 2005;65(8):3011–6. doi: 10.1158/0008-5472.CAN-04-3624 15833825.

32. Li Y, Lin AW, Zhang X, Wang Y, Wang X, Goodrich DW. Cancer cells and normal cells differ in their requirements for Thoc1. Cancer Res. 2007;67(14):6657–64. doi: 10.1158/0008-5472.CAN-06-3234 17638875; PubMed Central PMCID: PMC2804983.

33. Xiong H, Pang J, Yang H, Dai M, Liu Y, Ou Y, et al. Activation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: implications for age-related hearing loss. Neurobiol Aging. 2015;36(4):1692–701. doi: 10.1016/j.neurobiolaging.2014.12.034 25638533.

34. Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D'Agostino RB Sr., et al. Trends in cardiovascular complications of diabetes. JAMA. 2004;292(20):2495–9. Epub 2004/11/25. doi: 10.1001/jama.292.20.2495 15562129.

35. Gong J, Wang X, Zhu C, Dong X, Zhang Q, Wang X, et al. Insm1a Regulates Motor Neuron Development in Zebrafish. Front Mol Neurosci. 2017;10:274. doi: 10.3389/fnmol.2017.00274 28894416; PubMed Central PMCID: PMC5581358.

36. Wang X, Ling CC, Li L, Qin Y, Qi J, Liu X, et al. MicroRNA-10a/10b represses a novel target gene mib1 to regulate angiogenesis. Cardiovascular research. 2016;110(1):140–50. doi: 10.1093/cvr/cvw023 26825552.

37. Zhang J, Qi J, Wu S, Peng L, Shi Y, Yang J, et al. Fatty Acid Binding Protein 11a Is Required for Brain Vessel Integrity in Zebrafish. Frontiers in physiology. 2017;8:214. doi: 10.3389/fphys.2017.00214 28443032; PubMed Central PMCID: PMC5387095.

38. Huang Y, Wang X, Xu M, Liu M, Liu D. Nonmuscle myosin II-B (myh10) expression analysis during zebrafish embryonic development. Gene expression patterns: GEP. 2013;13(7):265–70. Epub 2013/05/15. S1567-133X(13)00043-4 [pii] doi: 10.1016/j.gep.2013.04.005 23665442.

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PLOS Genetics

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