Table S3. Genetic factors proposed to influence age-related or noise-induced hearing loss susceptibility. Candidate mouse and human genes, disrupted functions proposed to be caused by their mutations, and representative references to studies that have suggested or tested possible connections with either age-related (AHL) or noise-induced (NIHL) hearing loss.

Mouse gene / Allele / Effect / Proposed gene function / References
Actg1 / targeted KO / AHL / maintain stereocilia integrity / 1
Actb / conditional KO / AHL / maintain stereocilia integrity / 2
Adipoq / targeted KO / AHL / prevent apoptosis, promote cochlear blood flow / 3
Atp1a1, Atp1a2, Slc12a2 / het for KO / AHL / inner ear potassium homeostasis, endocochlear potential / 4
Atp2b2 / het for dfw / NIHL / inner ear calcium homeostasis / 5,6
Bak1 / targeted KO / delays AHL / reduce mitochondrial apoptosis / 7
Barhl1 / targeted KO / AHL / hair cell maintenance / 8
Cacna1h / targeted KO / delays AHL / calcium toxicity / 9
Cdh23 / ahl, strain variant / AHL, NIHL / stereocilia tip link integrity / 10,11
Cdhl23/Pcdh15 / digenic heterozygotes / AHL / hair bundle integrity / 12
Cdkn2d / targeted KO / AHL / hair cell re-entry into cell cycle / 13
Chrnb2 / targeted KO / AHL / efferent system maintenance of spiral ganglion neurons / 14
Cisd2 / targeted KO / AHL / mitochondrial integrity, premature aging / 15
Coch / targeted knock-in / AHL / extracellular matrix? / 16
Col9a1 / targeted KO / AHL / integrity of tectorial membrane / 17
Cs / ahl4, A/J strain variant / AHL / impaired mitochondrial function / 18
Dfnb59 (PJKV) / targeted KO / NIHL / adaptive proliferation of peroxisomes / 19
Eps8l2 / targeted KO / AHL / stereocilia maintenance / 20
Ercc1 / hypomorphic allele / AHL / DNA-repair deficient / 21
Esr2 / targeted KO / AHL / estrogen-related / 22
Fbxo2
Skp1a / targeted KO / AHL / protein quality control in cochlea / 23
Fscn2 / ahl8, DBA/2J variant / AHL / maintain stereocilia integrity / 24
Gabr-a5,b2,b3 / targeted KO / AHL / efferent system maintenance of hair cells and neurons / 25
Ggt1 / dwg mutation / AHL / glutathione and cysteine homeostasis / 26
Gipc3 / ahl5, strain variant / AHL / hair cell and spiral ganglion cell survival / 27
Gpx1 / targeted KO / NIHL / prevent oxidative stress / 28
Hsf1 / targeted KO / NIHL / heat shock protein expression / 29,30
Kcnma1 / targeted KO / AHL / regulate OHC depolarization / 31
Kcnq4 / targeted KO / AHL / regulate OHC depolarization / 32
miRNAs / differential expression / AHL / regulation of mRNA targets / 33
mt-Tr / A/J mtDNA variant / AHL / impair mitochondrial function / 34
Mmp7 / targeted KO / NIHL / regulate cochlear responses to acoustic overstimulation / 35
Nfe2l2 (Nrf2) / targeted KO / AHL / loss of antioxidant enzyme expression / 36
Nfkb1 / targeted KO / AHL, NIHL / survival of spiral ganglion cells / 37
Ngfr / targeted hypomorph / AHL / survival of spiral ganglion cells / 38
Nox3 / het mutation / NIHL / limiting inflammatory response / 39
Ocm / targeted KO / AHL / hair cell Ca++ buffer / 40
Otos / targeted KO / AHL / fibrocyte integrity / 41
P2rx2 / targeted KO / AHL, NIHL / cochlear membrane permeability / 42
Polg / targeted knock-in / AHL / accumulation of mtDNA mutations / 43
Prdx3 / siRNA targeting / NIHL / oxidative stress / 44
Prkg1 and Pde5 / targeted KO / NIHL / cGMP facilitated protection of hair cells / 45
Ret / het for knock-in / AHL / survival of spiral ganglion neurons / 46
Sirt3 / targeted KO / AHL / mitochondrial oxidative damage / 47
Slc44a2 / targeted KO / AHL / long term survival of hair cells and spiral ganglion cells / 48
Smad5 / het for KO / AHL / hair cell apoptosis / 49
Sod1 / targeted KO / AHL, NIHL / oxidative stress / 50
Thrb / β1 isoform KO / AHL / hair cell maintenance / 51
Trpv4 / targeted KO / AHL, NIHL / increased cochlear vulnerability / 52
Vasp / targeted KO / NIHL / pillar cells – actin cytoskeleton? / 53
Vezt / conditional KO / AHL, NIHL / hair cell – supporting cell junctions / 54
Human gene / Allele / Effect / Proposed gene function / References
ACTG1 / DFNA20/26 / AHL / hair cell maintenance and repair / 55
APOE / ε4 allele / AHL / protective effects / 56
CDH23 / SNPs / NIHL / tip link integrity / 57,58
COCH / DFNA9 / AHL / extracellular matrix / 59
DFNA5 / DFNA5 / AHL / dominant, progressive / 60
DFNB59 / PJKV / NIHL / adaptive proliferation of peroxisomes / 19
ESRRG / SNPs / AHL / estrogen-related / 61
GIPC3 / DFNB15/DFNB95 / AHL / hair cell and spiral ganglion cell survival / 27
GRHL2 / DFNA28, intron 1 SNP / AHL / cochlear epithelial cell maintenance? / 62
GRM7 / SNPs / AHL / susceptibility to glutamate excitotoxicity / 63
GSTT1, GSTM1, GSTP1 / SNPs / AHL, NIHL / oxidative stress, glutathione deficiency / 64,65
HSP70 / SNPs / NIHL / Noise-induced expression/protection / 66
KCNE1, KCNQ1, KCNQ4 / SNPs / NIHL / potassium recycling / 67
KCNQ4 / DFNA2, SNPs / AHL / potassium recycling, regulate OHC depolarization / 68,69
MYO6 / DFNA22, missense / AHL / dominant, progressive / 70
NAT2 / SNPS / AHL / oxidative stress / 65,71
TJP2 / DFNA51, duplication and overexpression, / AHL / apoptosis activating / 72
unknown / DFNA18 / AHL / unknown / 73
mtDNA / several / AHL / energy metabolism, oxidative stress / 74


References

1. Belyantseva, I.A. et al. {gamma}-Actin is required for cytoskeletal maintenance but not development. Proc Natl Acad Sci U S A (2009).

2. Perrin, B.J., Sonnemann, K.J. & Ervasti, J.M. beta-Actin and gamma-Actin Are Each Dispensable for Auditory Hair Cell Development But Required for Stereocilia Maintenance. PLoS Genet 6, e1001158 (2010).

3. Tanigawa, T. et al. Adiponectin deficiency exacerbates age-related hearing impairment. Cell Death Dis 5, e1189 (2014).

4. Diaz, R.C. et al. Conservation of hearing by simultaneous mutation of Na,K-ATPase and NKCC1. J Assoc Res Otolaryngol 8, 422-34 (2007).

5. Kozel, P.J., Davis, R.R., Krieg, E.F., Shull, G.E. & Erway, L.C. Deficiency in plasma membrane calcium ATPase isoform 2 increases susceptibility to noise-induced hearing loss in mice. Hear Res 164, 231-9 (2002).

6. Zheng, Q.Y. & Johnson, K.R. Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice. Hear Res 154, 45-53 (2001).

7. Someya, S. 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).

8. Li, S. et al. Hearing loss caused by progressive degeneration of cochlear hair cells in mice deficient for the Barhl1 homeobox gene. Development 129, 3523-3532. (2002).

9. Lei, D. et al. Anti-epileptic drugs delay age-related loss of spiral ganglion neurons via T-type calcium channel. Hear Res 278, 106-12 (2011).

10. Noben-Trauth, K., Zheng, Q.Y. & Johnson, K.R. Association of cadherin 23 with polygenic inheritance and genetic modification of sensorineural hearing loss. Nat Genet 35, 21-23 (2003).

11. Schwander, M. et al. A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells. Proc Natl Acad Sci U S A 106, 5252-7 (2009).

12. Zheng, Q.Y. et al. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet 14, 103-11 (2005).

13. Chen, P. et al. Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nat Cell Biol (2003).

14. Bao, J. et al. Requirement of nicotinic acetylcholine receptor subunit beta2 in the maintenance of spiral ganglion neurons during aging. J Neurosci 25, 3041-5 (2005).

15. Chen, Y.F. et al. Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev 23, 1183-94 (2009).

16. Robertson, N.G. et al. A targeted Coch missense mutation: a knock-in mouse model for DFNA9 late-onset hearing loss and vestibular dysfunction. Hum Mol Genet 17, 3426-34 (2008).

17. Suzuki, N. et al. Type IX collagen knock-out mouse shows progressive hearing loss. Neurosci Res 51, 293-8 (2005).

18. Johnson, K.R., Gagnon, L.H., Longo-Guess, C. & Kane, K.L. Association of a citrate synthase missense mutation with age-related hearing loss in A/J mice. Neurobiology of Aging 33, 1720-9 (2012).

19. Delmaghani, S. et al. Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes. Cell 163, 894-906 (2015).

20. Furness, D.N. et al. Progressive hearing loss and gradual deterioration of sensory hair bundles in the ears of mice lacking the actin-binding protein Eps8L2. Proc Natl Acad Sci U S A 110, 13898-903 (2013).

21. Spoor, M. et al. Accelerated loss of hearing and vision in the DNA-repair deficient Ercc1(delta/-) mouse. Mechanisms of Ageing and Development (2012).

22. Simonoska, R. et al. Inner ear pathology and loss of hearing in estrogen receptor beta deficient mice. J Endocrinol (2009).

23. Nelson, R.F. et al. Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit. J Neurosci 27, 5163-71 (2007).

24. Shin, J.B. et al. The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. J Neurosci 30, 9683-94 (2010).

25. Maison, S.F., Rosahl, T.W., Homanics, G.E. & Liberman, M.C. Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta. J Neurosci 26, 10315-26 (2006).

26. Ding, D. et al. N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in gamma-glutamyl transferase 1 deficient mice. Aging (Albany NY) (2016).

27. Charizopoulou, N. et al. Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human. Nat Commun 2, 201 (2011).

28. Ohlemiller, K.K., McFadden, S.L., Ding, D.L., Lear, P.M. & Ho, Y.S. Targeted mutation of the gene for cellular glutathione peroxidase (Gpx1) increases noise-induced hearing loss in mice. J Assoc Res Otolaryngol 1, 243-54 (2000).

29. Fairfield, D.A. et al. Heat shock factor 1-deficient mice exhibit decreased recovery of hearing following noise overstimulation. J Neurosci Res 81, 589-96 (2005).

30. Sugahara, K. et al. Heat shock transcription factor HSF1 is required for survival of sensory hair cells against acoustic overexposure. Hear Res 182, 88-96 (2003).

31. Ruttiger, L. et al. Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BKbeta1-subunit leads to progressive hearing loss. Proc Natl Acad Sci U S A 101, 12922-7 (2004).

32. Kharkovets, T. et al. Mice with altered KCNQ4 K(+) channels implicate sensory outer hair cells in human progressive deafness. Embo J 25, 642-652 (2006).

33. Zhang, Q. et al. Identifying MicroRNAs Involved in Degeneration of the Organ of Corti during Age-Related Hearing Loss. PLoS One 8, e62786 (2013).

34. Johnson, K.R., Zheng, Q.Y., Bykhovskaya, Y., Spirina, O. & Fischel-Ghodsian, N. A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice. Nat Genet 27, 191-4. (2001).

35. Hu, B.H. et al. Metalloproteinases and their associated genes contribute to the functional integrity and noise-induced damage in the cochlear sensory epithelium. J Neurosci 32, 14927-41 (2012).

36. Hoshino, T. et al. Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity. Biochemical and Biophysical Research Communications (2011).

37. Lang, H. et al. Nuclear factor kappaB deficiency is associated with auditory nerve degeneration and increased noise-induced hearing loss. J Neurosci 26, 3541-50 (2006).

38. Sato, T. et al. Progressive hearing loss in mice carrying a mutation in the p75 gene. Brain Res 1091, 224-34 (2006).

39. Lavinsky, J. et al. Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss. PLoS Genet 11, e1005094 (2015).

40. Tong, B. et al. Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice. J Neurosci 36, 1631-5 (2016).

41. Delprat, B. et al. Deafness and cochlear fibrocyte alterations in mice deficient for the inner ear protein otospiralin. Mol Cell Biol 25, 847-53 (2005).

42. Yan, D. et al. Mutation of the ATP-gated P2X2 receptor leads to progressive hearing loss and increased susceptibility to noise. Proc Natl Acad Sci U S A 110, 2228-33 (2013).

43. Kujoth, G.C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481-4 (2005).

44. Chen, F.Q., Zheng, H.W., Schacht, J. & Sha, S.H. Mitochondrial peroxiredoxin 3 regulates sensory cell survival in the cochlea. PLoS One 8, e61999 (2013).

45. Jaumann, M. et al. cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function. Nature Medicine (2012).

46. Ohgami, N. et al. Partial impairment of c-Ret at tyrosine 1062 accelerates age-related hearing loss in mice. Neurobiology of Aging (2011).

47. Someya, S. et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143, 802-12 (2010).

48. Kommareddi, P. et al. Hair Cell Loss, Spiral Ganglion Degeneration, and Progressive Sensorineural Hearing Loss in Mice with Targeted Deletion of Slc44a2/Ctl2. J Assoc Res Otolaryngol (2015).

49. Yang, S.M. et al. Smad5 haploinsufficiency leads to hair cell and hearing loss. Dev Neurobiol (2008).