Aldh inhibitor restores auditory function in a mouse model of human deafness


Autoři: Guang-Jie Zhu aff001;  Sihao Gong aff001;  Deng-Bin Ma aff001;  Tao Tao aff001;  Wei-Qi He aff001;  Linqing Zhang aff001;  Fang Wang aff001;  Xiao-Yun Qian aff001;  Han Zhou aff001;  Chi Fan aff001;  Pei Wang aff001;  Xin Chen aff001;  Wei Zhao aff001;  Jie Sun aff001;  Huaqun Chen aff003;  Ye Wang aff004;  Xiang Gao aff001;  Jian Zuo aff005;  Min-Sheng Zhu aff001;  Xia Gao aff001;  Guoqiang Wan aff001
Působiště autorů: Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Department of Otorhinolaryngology, Provincial Key Discipline of the affiliated Drum Tower Hospital of Nanjing University and Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Studies, School of Medicine, Nanjing University, Nanj aff001;  Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Suda (CAM-SU) Genomic Resource Center, Medical College of Soochow University, Suzhou, China aff002;  College of Life Science, Nanjing Normal University, Nanjing, China aff003;  Nanjing MuCyte Biotechnology Co., Ltd., Nanjing, China aff004;  Department of Biomedical Sciences, School of Medicine, Creighton University, United States of America aff005;  Institute for Brain Sciences, Nanjing University, Nanjing, China aff006
Vyšlo v časopise: Aldh inhibitor restores auditory function in a mouse model of human deafness. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009040
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009040

Souhrn

Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.

Klíčová slova:

Cochlea – Deafness – Genetically modified animals – Haploinsufficiency – Mouse models – Outer hair cells – Sensory perception – Signal inhibition


Zdroje

1. Morton CC, Nance WE. Newborn hearing screening—a silent revolution. N Engl J Med. 2006;354(20):2151–64. Epub 2006/05/19. doi: 10.1056/NEJMra050700 16707752.

2. Smith RJ, Bale JF Jr., White KR. Sensorineural hearing loss in children. Lancet. 2005;365(9462):879–90. Epub 2005/03/09. doi: 10.1016/S0140-6736(05)71047-3 15752533.

3. Vahava O, Morell R, Lynch ED, Weiss S, Kagan ME, Ahituv N, et al. Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science. 1998;279(5358):1950–4. Epub 1998/04/16. doi: 10.1126/science.279.5358.1950 9506947.

4. He L, Pang X, Chen P, Wu H, Yang T. Mutation in the Hair Cell Specific Gene POU4F3 Is a Common Cause for Autosomal Dominant Nonsyndromic Hearing Loss in Chinese Hans. Neural Plast. 2016;2016:9890827. Epub 2017/01/06. doi: 10.1155/2016/9890827 28053790.

5. Kitano T, Miyagawa M, Nishio SY, Moteki H, Oda K, Ohyama K, et al. POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss. PLoS One. 2017;12(5):e0177636. Epub 2017/05/26. doi: 10.1371/journal.pone.0177636 28545070.

6. Clough RL, Sud R, Davis-Silberman N, Hertzano R, Avraham KB, Holley M, et al. Brn-3c (POU4F3) regulates BDNF and NT-3 promoter activity. Biochem Biophys Res Commun. 2004;324(1):372–81. Epub 2004/10/07. doi: 10.1016/j.bbrc.2004.09.074 15465029.

7. Hertzano R, Montcouquiol M, Rashi-Elkeles S, Elkon R, Yucel R, Frankel WN, et al. Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum Mol Genet. 2004;13(18):2143–53. Epub 2004/07/16. doi: 10.1093/hmg/ddh218 15254021.

8. Hertzano R, Dror AA, Montcouquiol M, Ahmed ZM, Ellsworth B, Camper S, et al. Lhx3, a LIM domain transcription factor, is regulated by Pou4f3 in the auditory but not in the vestibular system. Eur J Neurosci. 2007;25(4):999–1005. Epub 2007/03/03. doi: 10.1111/j.1460-9568.2007.05332.x 17331196.

9. Weiss S, Gottfried I, Mayrose I, Khare SL, Xiang M, Dawson SJ, et al. The DFNA15 deafness mutation affects POU4F3 protein stability, localization, and transcriptional activity. Molecular and cellular biology. 2003;23(22):7957–64. doi: 10.1128/mcb.23.22.7957-7964.2003 14585957

10. Collin RW, Chellappa R, Pauw RJ, Vriend G, Oostrik J, van Drunen W, et al. Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding. Hum Mutat. 2008;29(4):545–54. Epub 2008/01/30. doi: 10.1002/humu.20693 18228599

11. Frydman M, Vreugde S, Nageris BI, Weiss S, Vahava O, Avraham KB. Clinical characterization of genetic hearing loss caused by a mutation in the POU4F3 transcription factor. Archives of otolaryngology—head & neck surgery. 2000;126(5):633–7. doi: 10.1001/archotol.126.5.633 10807331.

12. Erkman L, McEvilly RJ, Luo L, Ryan AK, Hooshmand F, O’Connell SM, et al. Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature. 1996;381(6583):603–6. doi: 10.1038/381603a0 8637595.

13. Xiang M, Gan L, Li D, Chen ZY, Zhou L, O’Malley BW Jr., et al. Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development. Proc Natl Acad Sci U S A. 1997;94(17):9445–50. Epub 1997/08/19. doi: 10.1073/pnas.94.17.9445 9256502

14. Wan G, Ji L, Schrepfer T, Gong S, Wang GP, Corfas G. Synaptopathy as a Mechanism for Age-Related Vestibular Dysfunction in Mice. Front Aging Neurosci. 2019;11:156. Epub 2019/07/12. doi: 10.3389/fnagi.2019.00156 31293415.

15. Curthoys IS. Vestibular compensation and substitution. Curr Opin Neurol. 2000;13(1):27–30. Epub 2000/03/17. doi: 10.1097/00019052-200002000-00006 10719646.

16. Ma DB, Chen J, Xia Y, Zhu GJ, Ma XF, Zhou H, et al. Inhibition of Myo6 gene expression by coexpression of a mutant of transcription factor POU4F3 (BRN3C) in hair cells. Molecular medicine reports. 2014;9(4):1185–90. doi: 10.3892/mmr.2014.1953 24535414.

17. Towers ER, Kelly JJ, Sud R, Gale JE, Dawson SJ. Caprin-1 is a target of the deafness gene Pou4f3 and is recruited to stress granules in cochlear hair cells in response to ototoxic damage. Journal of cell science. 2011;124(Pt 7):1145–55. doi: 10.1242/jcs.076141 21402877

18. Tornari C, Towers ER, Gale JE, Dawson SJ. Regulation of the orphan nuclear receptor Nr2f2 by the DFNA15 deafness gene Pou4f3. PLoS One. 2014;9(11):e112247. doi: 10.1371/journal.pone.0112247 25372459

19. Zheng QY, Johnson KR, Erway LC. Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses. Hear Res. 1999;130(1–2):94–107. Epub 1999/05/13. doi: 10.1016/s0378-5955(99)00003-9 10320101.

20. Du H, Ye C, Wu D, Zang YY, Zhang L, Chen C, et al. The Cation Channel TMEM63B Is an Osmosensor Required for Hearing. Cell Rep. 2020;31(5):107596. Epub 2020/05/07. doi: 10.1016/j.celrep.2020.107596 32375046.

21. Masuda M, Dulon D, Pak K, Mullen LM, Li Y, Erkman L, et al. Regulation of POU4F3 gene expression in hair cells by 5' DNA in mice. Neuroscience. 2011;197:48–64. Epub 2011/10/01. doi: 10.1016/j.neuroscience.2011.09.033 21958861.

22. Ahmed M, Wong EY, Sun J, Xu J, Wang F, Xu PX. Eya1-Six1 interaction is sufficient to induce hair cell fate in the cochlea by activating Atoh1 expression in cooperation with Sox2. Dev Cell. 2012;22(2):377–90. Epub 2012/02/22. doi: 10.1016/j.devcel.2011.12.006 22340499.

23. Masuda M, Pak K, Chavez E, Ryan AF. TFE2 and GATA3 enhance induction of POU4F3 and myosin VIIa positive cells in nonsensory cochlear epithelium by ATOH1. Developmental biology. 2012;372(1):68–80. Epub 2012/09/19. doi: 10.1016/j.ydbio.2012.09.002 22985730.

24. Gross J, Angerstein M, Fuchs J, Stute K, Mazurek B. Expression analysis of prestin and selected transcription factors in newborn rats. Cell Mol Neurobiol. 2011;31(7):1089–101. Epub 2011/05/27. doi: 10.1007/s10571-011-9708-z 21614551.

25. Perz-Edwards A, Hardison NL, Linney E. Retinoic acid-mediated gene expression in transgenic reporter zebrafish. Developmental biology. 2001;229(1):89–101. doi: 10.1006/dbio.2000.9979 11133156.

26. Germain P, Gaudon C, Pogenberg V, Sanglier S, Van Dorsselaer A, Royer CA, et al. Differential action on coregulator interaction defines inverse retinoid agonists and neutral antagonists. Chem Biol. 2009;16(5):479–89. Epub 2009/05/30. doi: 10.1016/j.chembiol.2009.03.008 19477412.

27. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res. 2002;43(11):1773–808. Epub 2002/10/29. doi: 10.1194/jlr.r100015-jlr200 12401878.

28. White RJ, Nie Q, Lander AD, Schilling TF. Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biol. 2007;5(11):e304. Epub 2007/11/23. doi: 10.1371/journal.pbio.0050304 18031199.

29. Lee HK, Park HJ, Lee KY, Park R, Kim UK. A novel frameshift mutation of POU4F3 gene associated with autosomal dominant non-syndromic hearing loss. Biochem Biophys Res Commun. 2010;396(3):626–30. Epub 2010/05/04. doi: 10.1016/j.bbrc.2010.04.132 20434433.

30. Pauw RJ, van Drunen FJ, Collin RW, Huygen PL, Kremer H, Cremers CW. Audiometric characteristics of a Dutch family linked to DFNA15 with a novel mutation (p.L289F) in POU4F3. Archives of otolaryngology—head & neck surgery. 2008;134(3):294–300. doi: 10.1001/archotol.134.3.294 18347256.

31. de Heer AM, Huygen PL, Collin RW, Kremer H, Cremers CW. Mild and variable audiometric and vestibular features in a third DFNA15 family with a novel mutation in POU4F3. The Annals of otology, rhinology, and laryngology. 2009;118(4):313–20. doi: 10.1177/000348940911800413 19462854.

32. Freitas EL, Oiticica J, Silva AG, Bittar RS, Rosenberg C, Mingroni-Netto RC. Deletion of the entire POU4F3 gene in a familial case of autosomal dominant non-syndromic hearing loss. Eur J Med Genet. 2014;57(4):125–8. doi: 10.1016/j.ejmg.2014.02.006 24556497.

33. Rosenberg C, Freitas EL, Uehara DT, Auricchio MT, Costa SS, Oiticica J, et al. Short Report—Clinical Genetics Genomic copy number alterations in non-syndromic hearing loss. Clinical genetics. 2015. doi: 10.1111/cge.12683 26456090.

34. Kim HJ, Won HH, Park KJ, Hong SH, Ki CS, Cho SS, et al. SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15). PLoS One. 2013;8(11):e79063. Epub 2013/11/22. doi: 10.1371/journal.pone.0079063 24260153

35. Cai XZ, Li Y, Xia L, Peng Y, He CF, Jiang L, et al. Exome sequencing identifies POU4F3 as the causative gene for a large Chinese family with non-syndromic hearing loss. Journal of human genetics. 2016. doi: 10.1038/jhg.2016.102 27535032.

36. Baek JI, Oh SK, Kim DB, Choi SY, Kim UK, Lee KY, et al. Targeted massive parallel sequencing: the effective detection of novel causative mutations associated with hearing loss in small families. Orphanet J Rare Dis. 2012;7:60. doi: 10.1186/1750-1172-7-60 22938506

37. Mutai H, Suzuki N, Shimizu A, Torii C, Namba K, Morimoto N, et al. Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. Orphanet J Rare Dis. 2013;8:172. doi: 10.1186/1750-1172-8-172 24164807

38. Yang T, Wei X, Chai Y, Li L, Wu H. Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J Rare Dis. 2013;8:85. doi: 10.1186/1750-1172-8-85 23767834

39. Wei Q, Zhu H, Qian X, Chen Z, Yao J, Lu Y, et al. Targeted genomic capture and massively parallel sequencing to identify novel variants causing Chinese hereditary hearing loss. Journal of translational medicine. 2014;12:311. doi: 10.1186/s12967-014-0311-1 25388789.

40. Keithley EM, Erkman L, Bennett T, Lou L, Ryan AF. Effects of a hair cell transcription factor, Brn-3.1, gene deletion on homozygous and heterozygous mouse cochleas in adulthood and aging. Hear Res. 1999;134(1–2):71–6. Epub 1999/08/19. doi: 10.1016/s0378-5955(99)00070-2 10452377.

41. Fausti SA, Frey RH, Henry JA, Olson DJ, Schaffer HI. Early detection of ototoxicity using high-frequency, tone-burst-evoked auditory brainstem responses. Journal of the American Academy of Audiology. 1992;3(6):397–404. 1486202.

42. Stapells DR. Low-Frequency Hearing and the Auditory Brainstem Response. American journal of audiology. 1994;3(2):11–3. doi: 10.1044/1059-0889.0302.11 26661602.

43. McEvilly RJ, Erkman L, Luo L, Sawchenko PE, Ryan AF, Rosenfeld MG. Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. Nature. 1996;384(6609):574–7. Epub 1996/12/12. doi: 10.1038/384574a0 8955272.

44. Herr W, Sturm RA, Clerc RG, Corcoran LM, Baltimore D, Sharp PA, et al. The POU domain: a large conserved region in the mammalian pit-1, oct-1, oct-2, and Caenorhabditis elegans unc-86 gene products. Genes Dev. 1988;2(12A):1513–6. Epub 1988/12/01. doi: 10.1101/gad.2.12a.1513 3215510.

45. Huang L, Szymanska K, Jensen VL, Janecke AR, Innes AM, Davis EE, et al. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. American journal of human genetics. 2011;89(6):713–30. Epub 2011/12/14. doi: 10.1016/j.ajhg.2011.11.005 22152675.

46. Leygue E. Steroid receptor RNA activator (SRA1): unusual bifaceted gene products with suspected relevance to breast cancer. Nucl Recept Signal. 2007;5:e006. Epub 2007/08/22. doi: 10.1621/nrs.05006 17710122.

47. Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, et al. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem. 2011;286(18):16101–8. Epub 2011/04/02. doi: 10.1074/jbc.M110.193433 21454553.

48. Matharu N, Rattanasopha S, Tamura S, Maliskova L, Wang Y, Bernard A, et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science. 2019;363(6424). Epub 2018/12/14. doi: 10.1126/science.aau0629 30545847.

49. Huang N, Lee I, Marcotte EM, Hurles ME. Characterising and predicting haploinsufficiency in the human genome. PLoS Genet. 2010;6(10):e1001154. Epub 2010/10/27. doi: 10.1371/journal.pgen.1001154 20976243.

50. Hoeger B, Serwas NK, Boztug K. Human NF-kappaB1 Haploinsufficiency and Epstein-Barr Virus-Induced Disease-Molecular Mechanisms and Consequences. Front Immunol. 2017;8:1978. Epub 2018/02/07. doi: 10.3389/fimmu.2017.01978 29403474.

51. Tolson KP, Gemelli T, Gautron L, Elmquist JK, Zinn AR, Kublaoui BM. Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2010;30(10):3803–12. Epub 2010/03/12. doi: 10.1523/JNEUROSCI.5444-09.2010 20220015.

52. Das BC, Thapa P, Karki R, Das S, Mahapatra S, Liu TC, et al. Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014;22(2):673–83. Epub 2014/01/08. doi: 10.1016/j.bmc.2013.11.025 24393720.

53. Wang S, Yu J, Kane MA, Moise AR. Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair. Pharmacol Ther. 2020;205:107415. Epub 2019/10/20. doi: 10.1016/j.pharmthera.2019.107415 31629008.

54. Pandya VB, Kumar S, Sachchidanand, Sharma R, Desai RC. Combating Autoimmune Diseases With Retinoic Acid Receptor-Related Orphan Receptor-gamma (RORgamma or RORc) Inhibitors: Hits and Misses. J Med Chem. 2018;61(24):10976–95. Epub 2018/07/17. doi: 10.1021/acs.jmedchem.8b00588 30010338.

55. Mahmoud MI, Potter JJ, Colvin OM, Hilton J, Mezey E. Effect of 4-(diethylamino)benzaldehyde on ethanol metabolism in mice. Alcohol Clin Exp Res. 1993;17(6):1223–7. Epub 1993/12/01. doi: 10.1111/j.1530-0277.1993.tb05233.x 8116835.

56. Ahadome SD, Abraham DJ, Rayapureddi S, Saw VP, Saban DR, Calder VL, et al. Aldehyde dehydrogenase inhibition blocks mucosal fibrosis in human and mouse ocular scarring. JCI Insight. 2016;1(12):e87001. Epub 2016/10/05. doi: 10.1172/jci.insight.87001 27699226.

57. Kim RJ, Park JR, Roh KJ, Choi AR, Kim SR, Kim PH, et al. High aldehyde dehydrogenase activity enhances stem cell features in breast cancer cells by activating hypoxia-inducible factor-2alpha. Cancer Lett. 2013;333(1):18–31. Epub 2012/11/24. doi: 10.1016/j.canlet.2012.11.026 23174107.

58. Thomas ML, de Antueno R, Coyle KM, Sultan M, Cruickshank BM, Giacomantonio MA, et al. Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3. Mol Oncol. 2016;10(9):1485–96. Epub 2016/09/07. doi: 10.1016/j.molonc.2016.08.004 27592281.

59. Keithley EM. Pathology and mechanisms of cochlear aging. J Neurosci Res. 2019. Epub 2019/05/09. doi: 10.1002/jnr.24439 31066107.

60. Owens KN, Cunningham DE, MacDonald G, Rubel EW, Raible DW, Pujol R. Ultrastructural analysis of aminoglycoside-induced hair cell death in the zebrafish lateral line reveals an early mitochondrial response. The Journal of comparative neurology. 2007;502(4):522–43. doi: 10.1002/cne.21345 17394157.

61. Scholtz AW, Kammen-Jolly K, Felder E, Hussl B, Rask-Andersen H, Schrott-Fischer A. Selective aspects of human pathology in high-tone hearing loss of the aging inner ear. Hear Res. 2001;157(1–2):77–86. Epub 2001/07/27. doi: 10.1016/s0378-5955(01)00279-9 11470187.

62. Ji L, Lee HJ, Wan G, Wang GP, Zhang L, Sajjakulnukit P, et al. Auditory metabolomics, an approach to identify acute molecular effects of noise trauma. Sci Rep. 2019;9(1):9273. Epub 2019/06/27. doi: 10.1038/s41598-019-45385-8 31239523.

63. Duran Alonso MB, Lopez Hernandez I, de la Fuente MA, Garcia-Sancho J, Giraldez F, Schimmang T. Transcription factor induced conversion of human fibroblasts towards the hair cell lineage. PLoS One. 2018;13(7):e0200210. Epub 2018/07/07. doi: 10.1371/journal.pone.0200210 29979748.

64. Walters BJ, Coak E, Dearman J, Bailey G, Yamashita T, Kuo B, et al. In Vivo Interplay between p27(Kip1), GATA3, ATOH1, and POU4F3 Converts Non-sensory Cells to Hair Cells in Adult Mice. Cell Rep. 2017;19(2):307–20. Epub 2017/04/14. doi: 10.1016/j.celrep.2017.03.044 28402854.

65. Costa A, Sanchez-Guardado L, Juniat S, Gale JE, Daudet N, Henrique D. Generation of sensory hair cells by genetic programming with a combination of transcription factors. Development. 2015;142(11):1948–59. Epub 2015/05/28. doi: 10.1242/dev.119149 26015538.

66. Zhu GJ, Wang F, Chen C, Xu L, Zhang WC, Fan C, et al. Myosin light-chain kinase is necessary for membrane homeostasis in cochlear inner hair cells. PLoS One. 2012;7(4):e34894. Epub 2012/04/10. doi: 10.1371/journal.pone.0034894 22485190.

67. Wan G, Corfas G. Transient auditory nerve demyelination as a new mechanism for hidden hearing loss. Nature communications. 2017;8:14487. Epub 2017/02/18. doi: 10.1038/ncomms14487 28211470.

68. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nature genetics. 2000;25(1):25–9. Epub 2000/05/10. doi: 10.1038/75556 10802651.

69. The Gene Ontology C. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 2019;47(D1):D330–D8. Epub 2018/11/06. doi: 10.1093/nar/gky1055 30395331.


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