Advertisement

Regulatory Mutations in Human Hereditary Deafness

  • Jonathan E. Bird
  • Thomas B. FriedmanEmail author
Chapter

Abstract

Moderate to profound deafness is a common sensory deficit that is estimated by the World Health Organization to affect more than 275 million people worldwide (WHO 2010). The etiology of hearing loss is varied and can include environmental noise, physical trauma to the head, infections, ototoxic compounds, and the natural aging process. Heritable hearing loss segregating as a Mendelian trait is thought to constitute but a fraction of cases; nonetheless, its study has yielded rich information about the biology of hearing and its pathophysiology. This chapter is a critical review of gene regulation in the auditory system and draws upon the dissection of human hereditary nonsyndromic hearing loss and relevant animal models. This body of work encompasses mutant alleles of transcription factors, promoters, long-range enhancers, and microRNAs that have been associated with hearing loss including genes such as ESSRB, EYA4, GRHL2, HGF, MIR96, POU3F4, and POU4F3. At the conclusion of this chapter, we speculate how future studies can capitalize on new sequencing technologies to broaden our knowledge of gene regulation in both normal hearing and deafness.

Keywords

Deafness Cochlea DFNA DFNB DFNX POU4F3 POU3F4 EYA4 MIR96 GRHL2 HGF ESRRB 

Abbreviations

3¢UTR

3¢ untranslated region

ABR

Auditory brainstem response

ALDH1A2

Aldehyde dehydrogenase 1 family member A2

ATP1B2

ATPase Na+/K + transporting, beta 2 polypeptide

bp

Base pair

CDH23

Cadherin-related 23

ChIP

Chromatin immunoprecipitation

ChIP-Seq

Chromatin immunoprecipitation coupled with massively parallel sequencing

DFNA

Nonsyndromic deafness autosomal dominant

DFNB

Nonsyndromic deafness autosomal recessive

DFNX

Nonsyndromic deafness X-linked

DPOAE

Distortion product otoacoustic emissions

E17

Embryonic day 17

ESRRB

Estrogen-related receptor

EUCOMM

European conditional mouse mutagenesis project

EYA4

Eyes absent Drosophila homolog 4

FACS

Fluorescence-activated cell sorting

FBXO11

F-box protein 11

GFP

Green fluorescent protein

GRHL2

Grainyhead-like 2

HGF

Hepatocyte growth factor

HNCR

Highly conserved noncoding regions

Hz

Hertz

iPS

Induced pluripotent stems cells

Kb

Kilobase

KCNE1

Potassium voltage-gated channel, Isk-related family, member 1

KCNQ1

Potassium voltage-gated channel, KQT-like subfamily, member 1

KOMP

NIH knockout mouse project

Mb

Megabase

MEFs

Mouse embryonic fibroblasts

NMD

Nonsense-mediated mRNA decay

POU3F4

POU class 3 homeobox 4

POU4F3

POU class 4 homeobox 3

POUH

POU homeodomain

PTGDS

Prostaglandin D2 synthase 21 kDa

PTPRQ

Protein tyrosine phosphatase receptor type, Q

RISC

RNA-induced silencing complex

RSPO3

R-spondin 3

SIX1

SIX homeobox 1

SLC12A2

Solute carrier family 12 member 2

SLC26A5

Solute carrier family 26 member 5

SNP

Single nucleotide polymorphism

STR

Short tandem repeats

WHO

World Health Organization

WNK4

Lysine-deficient protein kinase 4

WS2A

Waardenburg syndrome type 2A

Notes

Acknowledgements

We thank Lisa Cunningham, Dennis Drayna, Ronna Hertzano, Robert Morell and Julie Schultz for helpful discussions. JEB and TBF were supported by the National Institute on Deafness and Other Communication Disorders intramural research funds DC000039-15 at the National Institutes of Health.

References

  1. Abe Y, Oka A, Mizuguchi M, Igarashi T, Ishikawa S, Aburatani H, Yokoyama S, Asahara H, Nagao K, Yamada M, Miyashita T (2009) EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts with SIX3 both physically and functionally. Hum Mutat 30(10):E946–E955PubMedCrossRefGoogle Scholar
  2. Ahn KJ, Passero F Jr, Crenshaw EB III (2009) Otic mesenchyme expression of Cre recombinase directed by the inner ear enhancer of the Brn4/Pou3f4 gene. Genesis 47(3):137–141PubMedCrossRefGoogle Scholar
  3. Alvarado DM, Hawkins RD, Bashiardes S, Veile RA, Ku YC, Powder KE, Spriggs MK, Speck JD, Warchol ME, Lovett M (2011) An RNA interference-based screen of transcription factor genes identifies pathways necessary for sensory regeneration in the avian inner ear. J Neurosci 31(12):4535–4543PubMedCrossRefGoogle Scholar
  4. Ansar M, Din MA, Arshad M, Sohail M, Faiyaz-Ul-Haque M, Haque S, Ahmad W, Leal SM (2003) A novel autosomal recessive non-syndromic deafness locus (DFNB35) maps to 14q24.1–14q24.3 in large consanguineous kindred from Pakistan. Eur J Hum Genet 11(1):77–80PubMedCrossRefGoogle Scholar
  5. Avraham KB (2000) Dfna15. Adv Otorhinolaryngol 56:107–115PubMedCrossRefGoogle Scholar
  6. Ben Said M, Ayedi L, Mnejja M, Hakim B, Khalfallah A, Charfeddine I, Khifagi C, Turki K, Ayadi H, Benzina Z, Ghorbel A, Castillo ID, Masmoudi S, Aifa MH (2011) A novel missense mutation in the ESRRB gene causes DFNB35 hearing loss in a Tunisian family. Eur J Med Genet 54(6):e535–e541PubMedCrossRefGoogle Scholar
  7. Biggin MD, Tjian R (1988) Transcription factors that activate the Ultrabithorax promoter in developmentally staged extracts. Cell 53(5):699–711PubMedCrossRefGoogle Scholar
  8. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4(12):915–925PubMedCrossRefGoogle Scholar
  9. Bitner-Glindzicz M, Turnpenny P, Hoglund P, Kaariainen H, Sankila EM, van der Maarel SM, de Kok YJ, Ropers HH, Cremers FP, Pembrey M et al (1995) Further mutations in Brain 4 (POU3F4) clarify the phenotype in the X-linked deafness, DFN3. Hum Mol Genet 4(8):1467–1469PubMedCrossRefGoogle Scholar
  10. Blow MJ, McCulley DJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Bristow J, Ren B, Black BL, Rubin EM, Visel A, Pennacchio LA (2010) ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet 42(9):806–810PubMedCrossRefGoogle Scholar
  11. Blumberg B, Evans RM (1998) Orphan nuclear receptors – new ligands and new possibilities. Genes Dev 12(20):3149–3155PubMedCrossRefGoogle Scholar
  12. Boglev Y, Wilanowski T, Caddy J, Parekh V, Auden A, Darido C, Hislop NR, Cangkrama M, Ting SB, Jane SM (2011) The unique and cooperative roles of the grainy head-like transcription factors in epidermal development reflect unexpected target gene specificity. Dev Biol 349(2):512–522PubMedCrossRefGoogle Scholar
  13. Bonfig W, Krude H, Schmidt H (2011) A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature. Eur J Pediatr 170(8):1017–1021PubMedCrossRefGoogle Scholar
  14. Bonini NM, Leiserson WM, Benzer S (1998) Multiple roles of the eyes absent gene in Drosophila. Dev Biol 196(1):42–57PubMedCrossRefGoogle Scholar
  15. Borsani G, DeGrandi A, Ballabio A, Bulfone A, Bernard L, Banfi S, Gattuso C, Mariani M, Dixon M, Donnai D, Metcalfe K, Winter R, Robertson M, Axton R, Brown A, van Heyningen V, Hanson I (1999) EYA4, a novel vertebrate gene related to Drosophila eyes absent. Hum Mol Genet 8(1):11–23PubMedCrossRefGoogle Scholar
  16. Bray SJ, Kafatos FC (1991) Developmental function of Elf-1: an essential transcription factor during embryogenesis in Drosophila. Genes Dev 5(9):1672–1683PubMedCrossRefGoogle Scholar
  17. Brodersen P, Voinnet O (2009) Revisiting the principles of microRNA target recognition and mode of action. Nat Rev Mol Cell Biol 10(2):141–148PubMedCrossRefGoogle Scholar
  18. Brunner HG, van Bennekom A, Lambermon EM, Oei TL, Cremers WR, Wieringa B, Ropers HH (1988) The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK. Hum Genet 80(4):337–340PubMedCrossRefGoogle Scholar
  19. Budhram-Mahadeo V, Morris PJ, Lakin ND, Dawson SJ, Latchman DS (1996) The different activities of the two activation domains of the Brn-3a transcription factor are dependent on the context of the binding site. J Biol Chem 271(15):9108–9113PubMedCrossRefGoogle Scholar
  20. Caddy J, Wilanowski T, Darido C, Dworkin S, Ting SB, Zhao Q, Rank G, Auden A, Srivastava S, Papenfuss TA, Murdoch JN, Humbert PO, Parekh V, Boulos N, Weber T, Zuo J, Cunningham JM, Jane SM (2010) Epidermal wound repair is regulated by the planar cell polarity signaling pathway. Dev Cell 19(1):138–147PubMedCrossRefGoogle Scholar
  21. Chatterjee S, Kraus P, Lufkin T (2010) A symphony of inner ear developmental control genes. BMC Genet 11:68PubMedCrossRefGoogle Scholar
  22. Chen J, Nathans J (2007) Estrogen-related receptor beta/NR3B2 controls epithelial cell fate and endolymph production by the stria vascularis. Dev Cell 13(3):325–337PubMedCrossRefGoogle Scholar
  23. Christensen KL, Patrick AN, McCoy EL, Ford HL (2008) The six family of homeobox genes in development and cancer. Adv Cancer Res 101:93–126PubMedCrossRefGoogle Scholar
  24. Christodoulou F, Raible F, Tomer R, Simakov O, Trachana K, Klaus S, Snyman H, Hannon GJ, Bork P, Arendt D (2010) Ancient animal microRNAs and the evolution of tissue identity. Nature 463(7284):1084–1088PubMedCrossRefGoogle Scholar
  25. Collin RW, Chellappa R, Pauw RJ, Vriend G, Oostrik J, van Drunen W, Huygen PL, Admiraal R, Hoefsloot LH, Cremers FP, Xiang M, Cremers CW, Kremer H (2008a) Missense mutations in POU4F3 cause autosomal dominant hearing impairment DFNA15 and affect subcellular localization and DNA binding. Hum Mutat 29(4):545–554PubMedCrossRefGoogle Scholar
  26. Collin RW, Kalay E, Tariq M, Peters T, van der Zwaag B, Venselaar H, Oostrik J, Lee K, Ahmed ZM, Caylan R, Li Y, Spierenburg HA, Eyupoglu E, Heister A, Riazuddin S, Bahat E, Ansar M, Arslan S, Wollnik B, Brunner HG, Cremers CW, Karaguzel A, Ahmad W, Cremers FP, Vriend G, Friedman TB, Leal SM, Kremer H (2008b) Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. Am J Hum Genet 82(1):125–138PubMedCrossRefGoogle Scholar
  27. Cotanche DA, Kaiser CL (2010) Hair cell fate decisions in cochlear development and regeneration. Hear Res 266(1–2):18–25PubMedCrossRefGoogle Scholar
  28. Cremers FP, Cremers CW, Ropers HH (2000) The ins and outs of X-linked deafness type 3. Adv Otorhinolaryngol 56:184–195PubMedCrossRefGoogle Scholar
  29. Dawson SJ, Morris PJ, Latchman DS (1996) A single amino acid change converts an inhibitory transcription factor into an activator. J Biol Chem 271(20):11631–11633PubMedCrossRefGoogle Scholar
  30. de Kok YJ, Merkx GF, van der Maarel SM, Huber I, Malcolm S, Ropers HH, Cremers FP (1995a) A duplication/paracentric inversion associated with familial X-linked deafness (DFN3) suggests the presence of a regulatory element more than 400 kb upstream of the POU3F4 gene. Hum Mol Genet 4(11):2145–2150PubMedCrossRefGoogle Scholar
  31. de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP (1995b) Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science 267(5198):685–688PubMedCrossRefGoogle Scholar
  32. de Kok YJ, Vossenaar ER, Cremers CW, Dahl N, Laporte J, Hu LJ, Lacombe D, Fischel-Ghodsian N, Friedman RA, Parnes LS, Thorpe P, Bitner-Glindzicz M, Pander HJ, Heilbronner H, Graveline J, den Dunnen JT, Brunner HG, Ropers HH, Cremers FP (1996) Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum Mol Genet 5(9):1229–1235PubMedCrossRefGoogle Scholar
  33. De Leenheer EM, Huygen PL, Wayne S, Smith RJ, Cremers CW (2001) The DFNA10 phenotype. Ann Otol Rhinol Laryngol 110(9):861–866PubMedGoogle Scholar
  34. De Leenheer EM, Huygen PL, Wayne S, Verstreken M, Declau F, Van Camp G, Van de Heyning PH, Smith RJ, Cremers CW (2002) DFNA10/EYA4–the clinical picture. Adv Otorhinolaryngol 61:73–78PubMedGoogle Scholar
  35. de Pontual L, Yao E, Callier P, Faivre L, Drouin V, Cariou S, Van Haeringen A, Genevieve D, Goldenberg A, Oufadem M, Manouvrier S, Munnich A, Vidigal JA, Vekemans M, Lyonnet S, Henrion-Caude A, Ventura A, Amiel J (2011) Germline deletion of the mIR-17∼92 cluster causes skeletal and growth defects in humans. Nat Genet 43(10):1026–1030PubMedCrossRefGoogle Scholar
  36. Depreux FF, Darrow K, Conner DA, Eavey RD, Liberman MC, Seidman CE, Seidman JG (2008) Eya4-deficient mice are a model for heritable otitis media. J Clin Invest 118(2):651–658PubMedGoogle Scholar
  37. Ding S, Wu X, Li G, Han M, Zhuang Y, Xu T (2005) Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122(3):473–483PubMedCrossRefGoogle Scholar
  38. Doetzlhofer A, White P, Lee YS, Groves A, Segil N (2006) Prospective identification and purification of hair cell and supporting cell progenitors from the embryonic cochlea. Brain Res 1091(1):282–288PubMedCrossRefGoogle Scholar
  39. Elkan-Miller T, Ulitsky I, Hertzano R, Rudnicki A, Dror AA, Lenz DR, Elkon R, Irmler M, Beckers J, Shamir R, Avraham KB (2011) Integration of transcriptomics, proteomics, and microRNA analyses reveals novel microRNA regulation of targets in the mammalian inner ear. PLoS One 6(4):e18195PubMedCrossRefGoogle Scholar
  40. Erkman L, McEvilly RJ, Luo L, Ryan AK, Hooshmand F, O’Connell SM, Keithley EM, Rapaport DH, Ryan AF, Rosenfeld MG (1996) Role of transcription factors Brn-3.1 and Brn-3.2 in auditory and visual system development. Nature 381(6583):603–606PubMedCrossRefGoogle Scholar
  41. Feingold M, Hall BD, Lacassie Y, Martinez-Frias ML (1997) Syndrome of microcephaly, facial and hand abnormalities, tracheoesophageal fistula, duodenal atresia, and developmental delay. Am J Med Genet 69(3):245–249PubMedCrossRefGoogle Scholar
  42. Feng B, Jiang J, Kraus P, Ng JH, Heng JC, Chan YS, Yaw LP, Zhang W, Loh YH, Han J, Vega VB, Cacheux-Rataboul V, Lim B, Lufkin T, Ng HH (2009) Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol 11(2):197–203PubMedCrossRefGoogle Scholar
  43. Fettiplace R, Hackney CM (2006) The sensory and motor roles of auditory hair cells. Nat Rev Neurosci 7(1):19–29PubMedCrossRefGoogle Scholar
  44. Forrest D, Reh TA, Rusch A (2002) Neurodevelopmental control by thyroid hormone receptors. Curr Opin Neurobiol 12(1):49–56PubMedCrossRefGoogle Scholar
  45. Friedman LM, Avraham KB (2009) MicroRNAs and epigenetic regulation in the mammalian inner ear: implications for deafness. Mamm Genome 20(9–10):581–603PubMedCrossRefGoogle Scholar
  46. Friedman LM, Dror AA, Mor E, Tenne T, Toren G, Satoh T, Biesemeier DJ, Shomron N, Fekete DM, Hornstein E, Avraham KB (2009) MicroRNAs are essential for development and function of inner ear hair cells in vertebrates. Proc Natl Acad Sci USA 106(19):7915–7920PubMedCrossRefGoogle Scholar
  47. Friedman T, Battey J, Kachar B, Riazuddin S, Noben-Trauth K, Griffith A, Wilcox E (2000) Modifier genes of hereditary hearing loss. Curr Opin Neurobiol 10(4):487–493PubMedCrossRefGoogle Scholar
  48. Friedman TB, Liang Y, Weber JL, Hinnant JT, Barber TD, Winata S, Arhya IN, Asher JH Jr (1995) A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nat Genet 9(1):86–91PubMedCrossRefGoogle Scholar
  49. Friedman TB, Schultz JM, Ahmed ZM, Tsilou ET, Brewer CC (2011) Usher syndrome: hearing loss with vision loss. Adv Otorhinolaryngol 70:56–65PubMedGoogle Scholar
  50. Frolenkov GI, Belyantseva IA, Friedman TB, Griffith AJ (2004) Genetic insights into the morphogenesis of inner ear hair cells. Nat Rev Genet 5(7):489–498PubMedCrossRefGoogle Scholar
  51. Goodyear RJ, Richardson GP (2003) A novel antigen sensitive to calcium chelation that is associated with the tip links and kinocilial links of sensory hair bundles. J Neurosci 23(12):4878–4887PubMedGoogle Scholar
  52. Guo H, Ingolia NT, Weissman JS, Bartel DP (2010) Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466(7308):835–840PubMedCrossRefGoogle Scholar
  53. Han Y, Mu Y, Li X, Xu P, Tong J, Liu Z, Ma T, Zeng G, Yang S, Du J, Meng A (2011) Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28. Hum Mol Genet 20(16):3213–3226PubMedCrossRefGoogle Scholar
  54. Hanson IM (2001) Mammalian homologues of the Drosophila eye specification genes. Semin Cell Dev Biol 12(6):475–484PubMedCrossRefGoogle Scholar
  55. Hardisty-Hughes RE, Parker A, Brown SD (2010) A hearing and vestibular phenotyping pipeline to identify mouse mutants with hearing impairment. Nat Protoc 5(1):177–190PubMedCrossRefGoogle Scholar
  56. Hawkins RD, Bashiardes S, Powder KE, Sajan SA, Bhonagiri V, Alvarado DM, Speck J, Warchol ME, Lovett M (2007) Large scale gene expression profiles of regenerating inner ear sensory epithelia. PLoS One 2(6):e525PubMedCrossRefGoogle Scholar
  57. Hawkins RD, Helms CA, Winston JB, Warchol ME, Lovett M (2006) Applying genomics to the avian inner ear: development of subtractive cDNA resources for exploring sensory function and hair cell regeneration. Genomics 87(6):801–808PubMedCrossRefGoogle Scholar
  58. Henderson DH, Bielefeld E (2008) Patterns and mechanisms of noise-induced cochlear pathology. In: Schacht J, Fay R (eds) Auditory trauma, protection and repair, vol 31. Springer, DordrechtGoogle Scholar
  59. Heng JC, Orlov YL, Ng HH (2010) Transcription factors for the modulation of pluripotency and reprogramming. Cold Spring Harb Symp Quant Biol 75:37–244CrossRefGoogle Scholar
  60. Hertzano R, Dror AA, Montcouquiol M, Ahmed ZM, Ellsworth B, Camper S, Friedman TB, Kelley MW, Avraham KB (2007) Lhx3, a LIM domain transcription factor, is regulated by Pou4f3 in the auditory but not in the vestibular system. Eur J Neurosci 25(4):999–1005PubMedCrossRefGoogle Scholar
  61. Hertzano R, Elkon R, Kurima K, Morrisson A, Chan SL, Sallin M, Biedlingmaier A, Darling DS, Griffith AJ, Eisenman DJ, Strome SE (2011) Cell type-specific transcriptome analysis reveals a major role for Zeb1 and miR-200b in mouse inner ear morphogenesis. PLoS Genet 7(9):e1002309PubMedCrossRefGoogle Scholar
  62. Hertzano R, Montcouquiol M, Rashi-Elkeles S, Elkon R, Yucel R, Frankel WN, Rechavi G, Moroy T, Friedman TB, Kelley MW, Avraham KB (2004) Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene. Hum Mol Genet 13(18):2143–2153PubMedCrossRefGoogle Scholar
  63. Hertzano R, Puligilla C, Chan SL, Timothy C, Depireux DA, Ahmed Z, Wolf J, Eisenman DJ, Friedman TB, Riazuddin S, Kelley MW, Strome SE (2010) CD44 is a marker for the outer ­pillar cells in the early postnatal mouse inner ear. J Assoc Res Otolaryngol 11(3):407–418PubMedCrossRefGoogle Scholar
  64. Jemc J, Rebay I (2007) The eyes absent family of phosphotyrosine phosphatases: properties and roles in developmental regulation of transcription. Annu Rev Biochem 76:513–538PubMedCrossRefGoogle Scholar
  65. Jero J, Coling DE, Lalwani AK (2001) The use of Preyer’s reflex in evaluation of hearing in mice. Acta Otolaryngol 121(5):585–589PubMedCrossRefGoogle Scholar
  66. Kelley MW, Wu DK (2005) Development of the inner ear. Springer, New YorkCrossRefGoogle Scholar
  67. Kemp LE, Mulloy B, Gherardi E (2006) Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors. Biochem Soc Trans 34(Pt 3):414–417PubMedGoogle Scholar
  68. Kleinjan DJ, van Heyningen V (1998) Position effect in human genetic disease. Hum Mol Genet 7(10):1611–1618PubMedCrossRefGoogle Scholar
  69. Kokubu C, Horie K, Abe K, Ikeda R, Mizuno S, Uno Y, Ogiwara S, Ohtsuka M, Isotani A, Okabe M, Imai K, Takeda J (2009) A transposon-based chromosomal engineering method to survey a large cis-regulatory landscape in mice. Nat Genet 41(8):946–952PubMedCrossRefGoogle Scholar
  70. Kuhn S, Johnson SL, Furness DN, Chen J, Ingham N, Hilton JM, Steffes G, Lewis MA, Zampini V, Hackney CM, Masetto S, Holley MC, Steel KP, Marcotti W (2011) miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells. Proc Natl Acad Sci USA 108(6):2355–2360PubMedCrossRefGoogle Scholar
  71. Kurima K, Hertzano R, Gavrilova O, Monahan K, Shpargel KB, Nadaraja G, Kawashima Y, Lee KY, Ito T, Higashi Y, Eisenman DJ, Strome SE, Griffith AJ (2011) A noncoding point mutation of zeb1 causes multiple developmental malformations and obesity in twirler mice. PLoS Genet 7(9):e1002307PubMedCrossRefGoogle Scholar
  72. Lee HK, Park HJ, Lee KY, Park R, Kim UK (2010) A novel frameshift mutation of POU4F3 gene associated with autosomal dominant non-syndromic hearing loss. Biochem Biophys Res Commun 396(3):626–630PubMedCrossRefGoogle Scholar
  73. Lewis MA, Quint E, Glazier AM, Fuchs H, De Angelis MH, Langford C, van Dongen S, Abreu-Goodger C, Piipari M, Redshaw N, Dalmay T, Moreno-Pelayo MA, Enright AJ, Steel KP (2009) An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice. Nat Genet 41(5):614–618PubMedCrossRefGoogle Scholar
  74. Li H, Fekete DM (2010) MicroRNAs in hair cell development and deafness. Curr Opin Otolaryngol Head Neck Surg 18(5):459–465PubMedCrossRefGoogle Scholar
  75. Li X, Oghi KA, Zhang J, Krones A, Bush KT, Glass CK, Nigam SK, Aggarwal AK, Maas R, Rose DW, Rosenfeld MG (2003) Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature 426(6964):247–254PubMedCrossRefGoogle Scholar
  76. Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H, Albrechtsen A, Andersen G, Cao H, Korneliussen T, Grarup N, Guo Y, Hellman I, Jin X, Li Q, Liu J, Liu X, Sparso T, Tang M, Wu H, Wu R, Yu C, Zheng H, Astrup A, Bolund L, Holmkvist J, Jorgensen T, Kristiansen K, Schmitz O, Schwartz TW, Zhang X, Li R, Yang H, Wang J, Hansen T, Pedersen O, Nielsen R (2010) Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 42(11):969–972PubMedCrossRefGoogle Scholar
  77. Lin CC, Liu LZ, Addison JB, Wonderlin WF, Ivanov AV, Ruppert JM (2011a) A KLF4-miRNA-206 autoregulatory feedback loop can promote or inhibit protein translation depending upon cell context. Mol Cell Biol 31(12):2513–2527PubMedCrossRefGoogle Scholar
  78. Lin YH, Wu CC, Hsu CJ, Hwang JH, Liu TC (2011b) The grainyhead-like 2 gene (GRHL2) single nucleotide polymorphism is not associated with age-related hearing impairment in Han Chinese. Laryngoscope 121(6):1303–1307PubMedCrossRefGoogle Scholar
  79. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O’Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 365(7):611–619PubMedCrossRefGoogle Scholar
  80. Luo J, Sladek R, Bader JA, Matthyssen A, Rossant J, Giguere V (1997) Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature 388(6644):778–782PubMedCrossRefGoogle Scholar
  81. Ma J, DeFrances MC, Zou C, Johnson C, Ferrell R, Zarnegar R (2009) Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer. J Clin Invest 119(3):478–491PubMedCrossRefGoogle Scholar
  82. MacArthur DG, Tyler-Smith C (2010) Loss-of-function variants in the genomes of healthy humans. Hum Mol Genet 19(R2):R125–R130PubMedCrossRefGoogle Scholar
  83. Mace KA, Pearson JC, McGinnis W (2005) An epidermal barrier wound repair pathway in Drosophila is mediated by grainy head. Science 308(5720):381–385PubMedCrossRefGoogle Scholar
  84. Makishima T, Madeo AC, Brewer CC, Zalewski CK, Butman JA, Sachdev V, Arai AE, Holbrook BM, Rosing DR, Griffith AJ (2007) Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: evidence for correlation of normal cardiac phenotype with truncating mutations of the Eya domain. Am J Med Genet A 143A(14):1592–1598PubMedCrossRefGoogle Scholar
  85. Mencia A, Modamio-Hoybjor S, Redshaw N, Morin M, Mayo-Merino F, Olavarrieta L, Aguirre LA, del Castillo I, Steel KP, Dalmay T, Moreno F, Moreno-Pelayo MA (2009) Mutations in the seed region of human miR-96 are responsible for nonsyndromic progressive hearing loss. Nat Genet 41(5):609–613PubMedCrossRefGoogle Scholar
  86. Minowa O, Ikeda K, Sugitani Y, Oshima T, Nakai S, Katori Y, Suzuki M, Furukawa M, Kawase T, Zheng Y, Ogura M, Asada Y, Watanabe K, Yamanaka H, Gotoh S, Nishi-Takeshima M, Sugimoto T, Kikuchi T, Takasaka T, Noda T (1999) Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness. Science 285(5432):1408–1411PubMedCrossRefGoogle Scholar
  87. Mitsunaga K, Araki K, Mizusaki H, Morohashi K, Haruna K, Nakagata N, Giguere V, Yamamura K, Abe K (2004) Loss of PGC-specific expression of the orphan nuclear receptor ERR-beta results in reduction of germ cell number in mouse embryos. Mech Dev 121(3):237–246PubMedCrossRefGoogle Scholar
  88. Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, del Castillo I, Chardenoux S, Morais D, Lathrop M, Petit C, Moreno F (2004) A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA50, maps to chromosome 7q32 between the DFNB17 and DFNB13 deafness loci. J Med Genet 41(2):e14PubMedCrossRefGoogle Scholar
  89. Mustapha M, Fang Q, Gong TW, Dolan DF, Raphael Y, Camper SA, Duncan RK (2009) Deafness and permanently reduced potassium channel gene expression and function in hypothyroid Pit1dw mutants. J Neurosci 29(4):1212–1223PubMedCrossRefGoogle Scholar
  90. Nakamura T, Sakai K, Matsumoto K (2011) Hepatocyte growth factor twenty years on: much more than a growth factor. J Gastroenterol Hepatol 26(Suppl 1):188–202PubMedCrossRefGoogle Scholar
  91. Naranjo S, Voesenek K, de la Calle-Mustienes E, Robert-Moreno A, Kokotas H, Grigoriadou M, Economides J, Van Camp G, Hilgert N, Moreno F, Alsina B, Petersen MB, Kremer H, Gomez-Skarmeta JL (2010) Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet 128(4):411–419PubMedCrossRefGoogle Scholar
  92. Nicolson T, Rusch A, Friedrich RW, Granato M, Ruppersberg JP, Nusslein-Volhard C (1998) Genetic analysis of vertebrate sensory hair cell mechanosensation: the zebrafish circler mutants. Neuron 20(2):271–283PubMedCrossRefGoogle Scholar
  93. Niu X, Canlon B (2002) Protective mechanisms of sound conditioning. Adv Otorhinolaryngol 59:96–105PubMedGoogle Scholar
  94. Noben-Trauth K, Zheng QY, Johnson KR (2003) Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nat Genet 35(1):21–23PubMedCrossRefGoogle Scholar
  95. Noben-Trauth K, Zheng QY, Johnson KR, Nishina PM (1997) mdfw: a deafness susceptibility locus that interacts with deaf waddler (dfw). Genomics 44(3):266–272PubMedCrossRefGoogle Scholar
  96. O’Neill ME, Marietta J, Nishimura D, Wayne S, Van Camp G, Van Laer L, Negrini C, Wilcox ER, Chen A, Fukushima K, Ni L, Sheffield VC, Smith RJ (1996) A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome 6. Hum Mol Genet 5(6):853–856PubMedCrossRefGoogle Scholar
  97. Ohlemiller KK, Frisna RD (2008) Age-related hearing loss and its cellular and molecular bases. In: Schacht J, Faty R (eds) Auditory trauma, protection, and repair, vol 31. Springer, DordrechtGoogle Scholar
  98. Ohto H, Kamada S, Tago K, Tominaga SI, Ozaki H, Sato S, Kawakami K (1999) Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya. Mol Cell Biol 19(10):6815–6824PubMedGoogle Scholar
  99. Okabe Y, Sano T, Nagata S (2009) Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature 460(7254):520–524PubMedGoogle Scholar
  100. Orom UA, Nielsen FC, Lund AH (2008) MicroRNA-10a binds the 5¢UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell 30(4):460–471PubMedCrossRefGoogle Scholar
  101. Oshima K, Shin K, Diensthuber M, Peng AW, Ricci AJ, Heller S (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141(4):704–716PubMedCrossRefGoogle Scholar
  102. Ostrowski S, Dierick HA, Bejsovec A (2002) Genetic control of cuticle formation during embryonic development of Drosophila melanogaster. Genetics 161(1):171–182PubMedGoogle Scholar
  103. Owens KN, Santos F, Roberts B, Linbo T, Coffin AB, Knisely AJ, Simon JA, Rubel EW, Raible DW (2008) Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death. PLoS Genet 4(2):e1000020PubMedCrossRefGoogle Scholar
  104. Peters LM, Anderson DW, Griffith AJ, Grundfast KM, San Agustin TB, Madeo AC, Friedman TB, Morell RJ (2002) Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28. Hum Mol Genet 11(23):2877–2885PubMedCrossRefGoogle Scholar
  105. Phaneuf D, Moscioni AD, LeClair C, Raper SE, Wilson JM (2004) Generation of a mouse expressing a conditional knockout of the hepatocyte growth factor gene: demonstration of impaired liver regeneration. DNA Cell Biol 23(9):592–603PubMedCrossRefGoogle Scholar
  106. Phillips K, Luisi B (2000) The virtuoso of versatility: POU proteins that flex to fit. J Mol Biol 302(5):1023–1039PubMedCrossRefGoogle Scholar
  107. Phippard D, Boyd Y, Reed V, Fisher G, Masson WK, Evans EP, Saunders JC, Crenshaw EB 3rd (2000) The sex-linked fidget mutation abolishes Brn4/Pou3f4 gene expression in the embryonic inner ear. Hum Mol Genet 9(1):79–85PubMedCrossRefGoogle Scholar
  108. Phippard D, Lu L, Lee D, Saunders JC, Crenshaw EB 3rd (1999) Targeted mutagenesis of the POU-domain gene Brn4/Pou3f4 causes developmental defects in the inner ear. J Neurosci 19(14):5980–5989PubMedGoogle Scholar
  109. Pyrgaki C, Liu A, Niswander L (2011) Grainyhead-like 2 regulates neural tube closure and adhesion molecule expression during neural fold fusion. Dev Biol 353(1):38–49PubMedCrossRefGoogle Scholar
  110. Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G, Rice S, Campos LS, Yusa K, Banerjee R, Li MA, de la Rosa J, Strong A, Lu D, Ellis P, Conte N, Yang FT, Liu P, Bradley A (2010) PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science 330(6007):1104–1107PubMedCrossRefGoogle Scholar
  111. Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT (2008) Novel mutations in LHX3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 17(14):2150–2159PubMedCrossRefGoogle Scholar
  112. Rayapureddi JP, Kattamuri C, Steinmetz BD, Frankfort BJ, Ostrin EJ, Mardon G, Hegde RS (2003) Eyes absent represents a class of protein tyrosine phosphatases. Nature 426(6964):295–298PubMedCrossRefGoogle Scholar
  113. Rehman AU, Morell RJ, Belyantseva IA, Khan SY, Boger ET, Shahzad M, Ahmed ZM, Riazuddin S, Khan SN, Friedman TB (2010) Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. Am J Hum Genet 86(3):378–388PubMedCrossRefGoogle Scholar
  114. Riazuddin S, Castelein CM, Ahmed ZM, Lalwani AK, Mastroianni MA, Naz S, Smith TN, Liburd NA, Friedman TB, Griffith AJ, Wilcox ER (2000) Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nat Genet 26(4):431–434PubMedCrossRefGoogle Scholar
  115. Riazuddin S, Nazli S, Ahmed ZM, Yang Y, Zulfiqar F, Shaikh RS, Zafar AU, Khan SN, Sabar F, Javid FT, Wilcox ER, Tsilou E, Boger ET, Sellers JR, Belyantseva IA, Friedman TB (2008) Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. Hum Mutat 29(4):502–511PubMedCrossRefGoogle Scholar
  116. Richardson GP, de Monvel JB, Petit C (2011) How the genetics of deafness illuminates auditory physiology. Annu Rev Physiol 73:311–334PubMedCrossRefGoogle Scholar
  117. Rivolta MN, Grix N, Lawlor P, Ashmore JF, Jagger DJ, Holley MC (1998) Auditory hair cell precursors immortalized from the mammalian inner ear. Proc Biol Sci 265(1406):1595–1603PubMedCrossRefGoogle Scholar
  118. Robert-Moreno A, Naranjo S, de la Calle-Mustienes E, Gomez-Skarmeta JL, Alsina B (2010) Characterization of new otic enhancers of the pou3f4 gene reveal distinct signaling pathway regulation and spatio-temporal patterns. PLoS One 5(12):e15907PubMedCrossRefGoogle Scholar
  119. Robertson G, Hirst M, Bainbridge M, Bilenky M, Zhao Y, Zeng T, Euskirchen G, Bernier B, Varhol R, Delaney A, Thiessen N, Griffith OL, He A, Marra M, Snyder M, Jones S (2007) Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing. Nat Methods 4(8):651–657PubMedCrossRefGoogle Scholar
  120. Rusch A, Ng L, Goodyear R, Oliver D, Lisoukov I, Vennstrom B, Richardson G, Kelley MW, Forrest D (2001) Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors. J Neurosci 21(24):9792–9800PubMedGoogle Scholar
  121. Rybak LP, Talaska AE, Schacht J (2008) Drug-induced hearing loss. In: Schacht J, Fay R (eds) Auditory trauma, protection, and repair, vol 31. Springer, DordrechtGoogle Scholar
  122. Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C (1995) Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373(6516):699–702PubMedCrossRefGoogle Scholar
  123. Schonberger J, Levy H, Grunig E, Sangwatanaroj S, Fatkin D, MacRae C, Stacker H, Halpin C, Eavey R, Philbin EF, Katus H, Seidman JG, Seidman CE (2000) Dilated cardiomyopathy and sensorineural hearing loss: a heritable syndrome that maps to 6q23-24. Circulation 101(15):1812–1818PubMedCrossRefGoogle Scholar
  124. Schonberger J, Wang L, Shin JT, Kim SD, Depreux FF, Zhu H, Zon L, Pizard A, Kim JB, Macrae CA, Mungall AJ, Seidman JG, Seidman CE (2005) Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet 37(4):418–422PubMedCrossRefGoogle Scholar
  125. Schultz JM (2006) Waardenburg syndrome. Semin Hear 27(3):171–181CrossRefGoogle Scholar
  126. Schultz JM, Khan SN, Ahmed ZM, Riazuddin S, Waryah AM, Chhatre D, Starost MF, Ploplis B, Buckley S, Velasquez D, Kabra M, Lee K, Hassan MJ, Ali G, Ansar M, Ghosh M, Wilcox ER, Ahmad W, Merlino G, Leal SM, Friedman TB, Morell RJ (2009) Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am J Hum Genet 85(1):25–39PubMedCrossRefGoogle Scholar
  127. Schultz JM, Yang Y, Caride AJ, Filoteo AG, Penheiter AR, Lagziel A, Morell RJ, Mohiddin SA, Fananapazir L, Madeo AC, Penniston JT, Griffith AJ (2005) Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med 352(15):1557–1564PubMedCrossRefGoogle Scholar
  128. Schwander M, Lopes V, Sczaniecka A, Gibbs D, Lillo C, Delano D, Tarantino LM, Wiltshire T, Williams DS, Muller U (2009) A novel allele of myosin VIIa reveals a critical function for the C-terminal FERM domain for melanosome transport in retinal pigment epithelial cells. J Neurosci 29(50):15810–15818PubMedCrossRefGoogle Scholar
  129. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (2011) A conditional knockout resource for the genome-wide study of mouse gene function. Nature 474(7351):337–342PubMedCrossRefGoogle Scholar
  130. Soukup GA (2009) Little but loud: small RNAs have a resounding affect on ear development. Brain Res 1277:104–114PubMedCrossRefGoogle Scholar
  131. Street VA, Li J, Robbins CA, Kallman JC (2011) A DNA variant within the MYO7A promoter regulates YY1 transcription factor binding and gene expression serving as a potential dominant DFNA11 auditory genetic modifier. J Biol Chem 286(17):15278–15286PubMedCrossRefGoogle Scholar
  132. Ting SB, Wilanowski T, Cerruti L, Zhao LL, Cunningham JM, Jane SM (2003) The identification and characterization of human sister-of-mammalian grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors. Biochem J 370(Pt 3):953–962PubMedCrossRefGoogle Scholar
  133. Tootle TL, Silver SJ, Davies EL, Newman V, Latek RR, Mills IA, Selengut JD, Parlikar BE, Rebay I (2003) The transcription factor Eyes absent is a protein tyrosine phosphatase. Nature 426(6964):299–302PubMedCrossRefGoogle Scholar
  134. Toriello HV, Reardon W, Gorlin RJ (2004) Hereditary hearing loss and its syndromes, vol 2. Oxford University Press, New YorkGoogle Scholar
  135. Towers ER, Kelly JJ, Sud R, Gale JE, Dawson SJ (2011) 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. J Cell Sci 124(Pt 7):1145–1155PubMedCrossRefGoogle Scholar
  136. Vahava O, Morell R, Lynch ED, Weiss S, Kagan ME, Ahituv N, Morrow JE, Lee MK, Skvorak AB, Morton CC, Blumenfeld A, Frydman M, Friedman TB, King MC, Avraham KB (1998) Mutation in transcription factor POU4F3 associated with inherited progressive hearing loss in humans. Science 279(5358):1950–1954PubMedCrossRefGoogle Scholar
  137. Van Laer L, Van Eyken E, Fransen E, Huyghe JR, Topsakal V, Hendrickx JJ, Hannula S, Maki-Torkko E, Jensen M, Demeester K, Baur M, Bonaconsa A, Mazzoli M, Espeso A, Verbruggen K, Huyghe J, Huygen P, Kunst S, Manninen M, Konings A, Diaz-Lacava AN, Steffens M, Wienker TF, Pyykko I, Cremers CW, Kremer H, Dhooge I, Stephens D, Orzan E, Pfister M, Bille M, Parving A, Sorri M, Van de Heyning PH, Van Camp G (2008) The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment. Hum Mol Genet 17(2):159–169PubMedCrossRefGoogle Scholar
  138. Verhoeven K, Fagerheim T, Prasad S, Wayne S, De Clau F, Balemans W, Verstreken M, Schatteman I, Solem B, Van de Heyning P, Tranebjarg L, Smith RJ, Van Camp G (2000) Refined localization and two additional linked families for the DFNA10 locus for nonsyndromic hearing impairment. Hum Genet 107(1):7–11PubMedCrossRefGoogle Scholar
  139. Verstreken M, Declau F, Schatteman I, Van Velzen D, Verhoeven K, Van Camp G, Willems PJ, Kuhweide EW, Verhaert E, D’Haese P, Wuyts FL, Van de Heyning PH (2000) Audiometric analysis of a Belgian family linked to the DFNA10 locus. Am J Otol 21(5):675–681PubMedGoogle Scholar
  140. Visel A, Blow MJ, Li Z, Zhang T, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Wright C, Chen F, Afzal V, Ren B, Rubin EM, Pennacchio LA (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457(7231):854–858PubMedCrossRefGoogle Scholar
  141. Wajid M, Abbasi AA, Ansar M, Pham TL, Yan K, Haque S, Ahmad W, Leal SM (2003) DFNB39, a recessive form of sensorineural hearing impairment, maps to chromosome 7q11.22–q21.12. Eur J Hum Genet 11(10):812–815PubMedCrossRefGoogle Scholar
  142. Wallis C, Ballo R, Wallis G, Beighton P, Goldblatt J (1988) X-linked mixed deafness with stapes fixation in a Mauritian kindred: linkage to Xq probe pDP34. Genomics 3(4):299–301PubMedCrossRefGoogle Scholar
  143. Wallis D, Hamblen M, Zhou Y, Venken KJ, Schumacher A, Grimes HL, Zoghbi HY, Orkin SH, Bellen HJ (2003) The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival. Development 130(1):221–232PubMedCrossRefGoogle Scholar
  144. Warchol ME (2011) Sensory regeneration in the vertebrate inner ear: differences at the levels of cells and species. Hear Res 273(1–2):72–79PubMedCrossRefGoogle Scholar
  145. Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, Tranebjarg L, Morton CC, Ryan AF, Van Camp G, Smith RJ (2001) Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet 10(3):195–200PubMedCrossRefGoogle Scholar
  146. Wegner M, Drolet DW, Rosenfeld MG (1993) POU-domain proteins: structure and function of developmental regulators. Curr Opin Cell Biol 5(3):488–498PubMedCrossRefGoogle Scholar
  147. Weiss S, Gottfried I, Mayrose I, Khare SL, Xiang M, Dawson SJ, Avraham KB (2003) The DFNA15 deafness mutation affects POU4F3 protein stability, localization, and transcriptional activity. Mol Cell Biol 23(22):7957–7964PubMedCrossRefGoogle Scholar
  148. Werth M, Walentin K, Aue A, Schonheit J, Wuebken A, Pode-Shakked N, Vilianovitch L, Erdmann B, Dekel B, Bader M, Barasch J, Rosenbauer F, Luft FC, Schmidt-Ott KM (2010) The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex. Development 137(22):3835–3845PubMedCrossRefGoogle Scholar
  149. Weston MD, Pierce ML, Jensen-Smith HC, Fritzsch B, Rocha-Sanchez S, Beisel KW, Soukup GA (2011) MicroRNA-183 family expression in hair cell development and requirement of microRNAs for hair cell maintenance and survival. Dev Dyn 240(4):808–819PubMedCrossRefGoogle Scholar
  150. Weston MD, Pierce ML, Rocha-Sanchez S, Beisel KW, Soukup GA (2006) MicroRNA gene expression in the mouse inner ear. Brain Res 1111(1):95–104PubMedCrossRefGoogle Scholar
  151. White PM, Doetzlhofer A, Lee YS, Groves AK, Segil N (2006) Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 441(7096):984–987PubMedCrossRefGoogle Scholar
  152. Whitehead RH, Robinson PS (2009) Establishment of conditionally immortalized epithelial cell lines from the intestinal tissue of adult normal and transgenic mice. Am J Physiol Gastrointest Liver Physiol 296(3):G455–G460PubMedCrossRefGoogle Scholar
  153. WHO (2010) Deafness and hearing impairment. Fact sheet #300Google Scholar
  154. Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E, Horvitz HR, Kauppinen S, Plasterk RH (2005) MicroRNA expression in zebrafish embryonic development. Science 309(5732):310–311PubMedCrossRefGoogle Scholar
  155. Wilanowski T, Tuckfield A, Cerruti L, O’Connell S, Saint R, Parekh V, Tao J, Cunningham JM, Jane SM (2002) A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead. Mech Dev 114(1–2):37–50PubMedCrossRefGoogle Scholar
  156. Winter H, Braig C, Zimmermann U, Engel J, Rohbock K, Knipper M (2007) Thyroid hormone receptor alpha1 is a critical regulator for the expression of ion channels during final differentiation of outer hair cells. Histochem Cell Biol 128(1):65–75PubMedCrossRefGoogle Scholar
  157. Xiang M, Gan L, Li D, Chen ZY, Zhou L, O’Malley BW Jr, Klein W, Nathans J (1997) Essential role of POU-domain factor Brn-3c in auditory and vestibular hair cell development. Proc Natl Acad Sci USA 94(17):9445–9450PubMedCrossRefGoogle Scholar
  158. Xiang M, Gao WQ, Hasson T, Shin JJ (1998) Requirement for Brn-3c in maturation and survival, but not in fate determination of inner ear hair cells. Development 125(20):3935–3946PubMedGoogle Scholar
  159. Xu S, Witmer PD, Lumayag S, Kovacs B, Valle D (2007) MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster. J Biol Chem 282(34):25053–25066PubMedCrossRefGoogle Scholar
  160. Zhou W, Liu Z, Wu J, Liu JH, Hyder SM, Antoniou E, Lubahn DB (2006) Identification and characterization of two novel splicing isoforms of human estrogen-related receptor beta. J Clin Endocrinol Metab 91(2):569–579PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Laboratory of Molecular GeneticsNational Institute on Deafness and Other Communication Disorders, National Institutes of HealthRockvilleUSA

Personalised recommendations