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HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice

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The most frequent sensory disorder worldwide is hearing impairment. It impacts over 5% of the world population (360 million persons), and is characterized by extreme genetic heterogeneity. Over 80 genes have been implicated in isolated (also referred to as ‘non-syndromic’) hearing loss, and abundant evidence supports the existence of many more ‘deafness-causing’ genes. In this study, we used a sequential screening strategy to first exclude causal mutations in known deafness-causing genes in a family segregating autosomal dominant non-syndromic hearing loss. We next turned to whole exome sequencing and identified a single variant—p.Arg185Pro in HOMER2—that segregated with the phenotype in the extended family. To validate the pathological significance of this mutation, we studied two animal models. In zebrafish, we overexpressed mutant HOMER2 and observed inner ear defects; and in mice we documented robust expression in stereocilia of cochlear hair cells and demonstrated that its absence causes early-onset progressive deafness. Our data offer novel insights into gene pathways essential for normal auditory function and the maintenance of cochlear hair cells.

Vyšlo v časopise: HOMER2, a Stereociliary Scaffolding Protein, Is Essential for Normal Hearing in Humans and Mice. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005137
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005137

Souhrn

The most frequent sensory disorder worldwide is hearing impairment. It impacts over 5% of the world population (360 million persons), and is characterized by extreme genetic heterogeneity. Over 80 genes have been implicated in isolated (also referred to as ‘non-syndromic’) hearing loss, and abundant evidence supports the existence of many more ‘deafness-causing’ genes. In this study, we used a sequential screening strategy to first exclude causal mutations in known deafness-causing genes in a family segregating autosomal dominant non-syndromic hearing loss. We next turned to whole exome sequencing and identified a single variant—p.Arg185Pro in HOMER2—that segregated with the phenotype in the extended family. To validate the pathological significance of this mutation, we studied two animal models. In zebrafish, we overexpressed mutant HOMER2 and observed inner ear defects; and in mice we documented robust expression in stereocilia of cochlear hair cells and demonstrated that its absence causes early-onset progressive deafness. Our data offer novel insights into gene pathways essential for normal auditory function and the maintenance of cochlear hair cells.

Zdroje

1. Avraham KB, Kanaan M (2012) Genomic advances for gene discovery in hereditary hearing loss. Journal of basic and clinical physiology and pharmacology 23 : 93–97. doi: 10.1515/jbcpp-2012-0033 22962211

2. Shearer AE, Smith RJ (2012) Genetics: advances in genetic testing for deafness. Curr Opin Pediatr 24 : 679–686. doi: 10.1097/MOP.0b013e3283588f5e 23042251

3. Stelma F, Bhutta MF (2014) Non-syndromic hereditary sensorineural hearing loss: review of the genes involved. The Journal of laryngology and otology 128 : 13–21. doi: 10.1017/S0022215113003265 24423691

4. Mammano F (2011) Ca2+ homeostasis defects and hereditary hearing loss. BioFactors 37 : 182–188. doi: 10.1002/biof.150 21698697

5. Jardin I, Lopez JJ, Berna-Erro A, Salido GM, Rosado JA (2013) Homer proteins in Ca(2)(+) entry. IUBMB life 65 : 497–504. doi: 10.1002/iub.1162 23554128

6. Worley PF, Zeng W, Huang G, Kim JY, Shin DM, Kim MS, et al. (2007) Homer proteins in Ca2+ signaling by excitable and non-excitable cells. Cell calcium 42 : 363–371. 17618683

7. Shiraishi-Yamaguchi Y, Furuichi T (2007) The Homer family proteins. Genome biology 8 : 206. 17316461

8. Kato A, Ozawa F, Saitoh Y, Fukazawa Y, Sugiyama H, Inokuchi K (1998) Novel members of the Vesl/Homer family of PDZ proteins that bind metabotropic glutamate receptors. The Journal of biological chemistry 273 : 23969–23975. 9727012

9. Shiraishi Y, Mizutani A, Bito H, Fujisawa K, Narumiya S, Mikoshiba K, et al. (1999) Cupidin, an isoform of Homer/Vesl, interacts with the actin cytoskeleton and activated rho family small GTPases and is expressed in developing mouse cerebellar granule cells. The Journal of neuroscience: the official journal of the Society for Neuroscience 19 : 8389–8400. 10493740

10. Shiraishi-Yamaguchi Y, Sato Y, Sakai R, Mizutani A, Knopfel T, Mori N, et al. (2009) Interaction of Cupidin/Homer2 with two actin cytoskeletal regulators, Cdc42 small GTPase and Drebrin, in dendritic spines. BMC neuroscience 10 : 25. doi: 10.1186/1471-2202-10-25 19309525

11. Hayashi MK, Ames HM, Hayashi Y (2006) Tetrameric hub structure of postsynaptic scaffolding protein homer. The Journal of neuroscience: the official journal of the Society for Neuroscience 26 : 8492–8501. 16914674

12. Kammermeier PJ, Xiao B, Tu JC, Worley PF, Ikeda SR (2000) Homer proteins regulate coupling of group I metabotropic glutamate receptors to N-type calcium and M-type potassium channels. The Journal of neuroscience: the official journal of the Society for Neuroscience 20 : 7238–7245. 11007880

13. Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, et al. (2003) Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114 : 777–789. 14505576

14. Kurnellas MP, Lee AK, Li H, Deng L, Ehrlich DJ, Elkabes S (2007) Molecular alterations in the cerebellum of the plasma membrane calcium ATPase 2 (PMCA2)-null mouse indicate abnormalities in Purkinje neurons. Molecular and cellular neurosciences 34 : 178–188. 17150372

15. Salm EJ, Thayer SA (2012) Homer proteins accelerate Ca2+ clearance mediated by the plasma membrane Ca2+ pump in hippocampal neurons. Biochemical and biophysical research communications 424 : 76–81. doi: 10.1016/j.bbrc.2012.06.069 22732411

16. Szumlinski KK, Kalivas PW, Worley PF (2006) Homer proteins: implications for neuropsychiatric disorders. Current opinion in neurobiology 16 : 251–257. 16704932

17. Foa L, Gasperini R (2009) Developmental roles for Homer: more than just a pretty scaffold. Journal of neurochemistry 108 : 1–10. doi: 10.1111/j.1471-4159.2009.05813.x 19222714

18. Ronesi JA, Collins KA, Hays SA, Tsai NP, Guo W, Birnbaum SG, et al. (2012) Disrupted Homer scaffolds mediate abnormal mGluR5 function in a mouse model of fragile X syndrome. Nature neuroscience 15 : 431–440, S431. doi: 10.1038/nn.3033 22267161

19. Szumlinski KK, Ary AW, Lominac KD (2008) Homers regulate drug-induced neuroplasticity: implications for addiction. Biochemical pharmacology 75 : 112–133. 17765204

20. Huygen PL, Pennings RJ, Cremers CW (2003) Characterizing and distinguishing progressive phenotypes in nonsyndromic autosomal dominant hearing impairment. Audiological Medicine 1 : 37–46.

21. Shearer AE, DeLuca AP, Hildebrand MS, Taylor KR, Gurrola J 2nd, Scherer S, et al. (2010) Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proceedings of the National Academy of Sciences of the United States of America 107 : 21104–21109. doi: 10.1073/pnas.1012989107 21078986

22. Azaiez H, Booth KT, Bu F, Huygen P, Shibata SB, Shearer AE, et al. (2014) TBC1D24 Mutation Causes Autosomal-Dominant Nonsyndromic Hearing Loss. Human mutation 10.1002/humu.22557.

23. Shiraishi Y, Mizutani A, Yuasa S, Mikoshiba K, Furuichi T (2004) Differential expression of Homer family proteins in the developing mouse brain. The Journal of comparative neurology 473 : 582–599. 15116392

24. Hertzano R, Elkon R, Kurima K, Morrisson A, Chan SL, Sallin M, et al. (2011) Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis. PLoS genetics 7: e1002309. doi: 10.1371/journal.pgen.1002309 21980309

25. Thisse B, Thisse, C. (2004) Fast Release Clones: A High Throughput Expression Analysis ZFIN Direct Data Submission (http://zfinorg).

26. Bottai D, Guzowski JF, Schwarz MK, Kang SH, Xiao B, Lanahan A, et al. (2002) Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression. The Journal of neuroscience: the official journal of the Society for Neuroscience 22 : 167–175.

27. Sala C, Roussignol G, Meldolesi J, Fagni L (2005) Key role of the postsynaptic density scaffold proteins Shank and Homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience 25 : 4587–4592. 15872106

28. Kammermeier PJ, Worley PF (2007) Homer 1a uncouples metabotropic glutamate receptor 5 from postsynaptic effectors. Proceedings of the National Academy of Sciences of the United States of America 104 : 6055–6060. 17389377

29. Kammermeier PJ (2008) Endogenous homer proteins regulate metabotropic glutamate receptor signaling in neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience 28 : 8560–8567. doi: 10.1523/JNEUROSCI.1830-08.2008 18716215

30. Tappe A, Kuner R (2006) Regulation of motor performance and striatal function by synaptic scaffolding proteins of the Homer1 family. Proceedings of the National Academy of Sciences of the United States of America 103 : 774–779. 16407107

31. Shin DM, Dehoff M, Luo X, Kang SH, Tu J, Nayak SK, et al. (2003) Homer 2 tunes G protein-coupled receptors stimulus intensity by regulating RGS proteins and PLCbeta GAP activities. The Journal of cell biology 162 : 293–303. 12860966

32. Szumlinski KK, Toda S, Middaugh LD, Worley PF, Kalivas PW (2003) Evidence for a relationship between Group 1 mGluR hypofunction and increased cocaine and ethanol sensitivity in Homer2 null mutant mice. Annals of the New York Academy of Sciences 1003 : 468–471. 14684491

33. Kalivas PW, Szumlinski KK, Worley P (2004) Homer2 gene deletion in mice produces a phenotype similar to chronic cocaine treated rats. Neurotoxicity research 6 : 385–387. 15545022

34. Cozzoli DK, Goulding SP, Zhang PW, Xiao B, Hu JH, Ary AW, et al. (2009) Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: functional implications for alcoholism. The Journal of neuroscience: the official journal of the Society for Neuroscience 29 : 8655–8668. doi: 10.1523/JNEUROSCI.5900-08.2009 19587272

35. Huang GN, Huso DL, Bouyain S, Tu J, McCorkell KA, May MJ, et al. (2008) NFAT binding and regulation of T cell activation by the cytoplasmic scaffolding Homer proteins. Science 319 : 476–481. doi: 10.1126/science.1151227 18218901

36. Ueyama T, Sakaguchi H, Nakamura T, Goto A, Morioka S, Shimizu A, et al. (2014) Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells. J Cell Sci 127 : 2040–2052. doi: 10.1242/jcs.143602 24610943

37. Quick K, Zhao J, Eijkelkamp N, Linley JE, Rugiero F, Cox JJ, et al. (2012) TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells. Open biology 2 : 120068. doi: 10.1098/rsob.120068 22724068

38. Yang YM, Lee J, Jo H, Park S, Chang I, Muallem S, et al. (2014) Homer2 protein regulates plasma membrane Ca(2)(+)-ATPase-mediated Ca(2)(+) signaling in mouse parotid gland acinar cells. The Journal of biological chemistry 289 : 24971–24979. doi: 10.1074/jbc.M114.577221 25049230

39. Dumont RA, Lins U, Filoteo AG, Penniston JT, Kachar B, Gillespie PG (2001) Plasma membrane Ca2+-ATPase isoform 2a is the PMCA of hair bundles. The Journal of neuroscience: the official journal of the Society for Neuroscience 21 : 5066–5078. 11438582

40. Shearer AE, Black-Ziegelbein EA, Hildebrand MS, Eppsteiner RW, Ravi H, Joshi S, et al. (2013) Advancing genetic testing for deafness with genomic technology. Journal of medical genetics 50 : 627–634. doi: 10.1136/jmedgenet-2013-101749 23804846

41. Westerfield M (1993) The Zebrafish Book: University of Oregon Press.

42. Soken H, Robinson BK, Goodman SS, Abbas PJ, Hansen MR, Kopelovich JC (2013) Mouse cochleostomy: a minimally invasive dorsal approach for modeling cochlear implantation. Laryngoscope 123: E109–115. doi: 10.1002/lary.24174 23674233

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