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Genes responsible for human hereditary deafness: symphony of a thousand

Abstract

Hearing loss is the most frequent sensory defect in humans. Dozens of genes may be responsible for the early onset forms of isolated deafness and several hundreds of syndromes with hearing loss have been described. Both the difficulties encountered by linkage analysis in families affected by isolated deafness and the paucity of data concerning the molecular components specifically involved in the peripheral auditory process, have long hampered the identification of genes responsible for hereditary hearing loss. Rapid progress is now being made in both fields. This should allow completion of major pieces of the jigsaw for understanding the development and function of the ear.

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References

  1. Denk, W., Holt, J.R., Shepherd, G.M.G. & Corey, D.P. Calcium imaging of single stereocilia in hair cells: localization of transduction channels at both ends of tip links. Neuron 15, 1311–1321 (1995).

    CAS  PubMed  Google Scholar 

  2. Hudspeth, A.J. & Gillespie, P.G. Pulling springs to tune transduction: adaptation by hair cells. Neuron 12, 1–9 (1994).

    CAS  PubMed  Google Scholar 

  3. Marazita, M.L. et al. Genetic epidemiological studies of early-onset deafness in the U.S. school-age population. Am. J. Med. Genet. 46, 486–491 (1993).

    CAS  PubMed  Google Scholar 

  4. Gorlin, R.J., Toriello, H.V. & Cohen, M.M. Hereditary hearing loss and its syndromes. (Oxford University Press, Oxford, 1995).

    Google Scholar 

  5. Chung, C.S., Robison, O.W. & Morton, N.E. A note on deaf mutism. Ann. Hum. Genet. 23, 357–366 (1959).

    CAS  PubMed  Google Scholar 

  6. Leon, P.E., Raventos, H., Lynch, E., Morrow, J. & King, M.-C. The gene for an inherited form of deafness maps to chromosome 5q31. Proc. Natl. Acad. Sci. USA 89, 5181–5184 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Reardon, W. et al. A multipedigree linkage study of X-linked deafness: linkage to Xq13–q21 and evidence for genetic heterogeneity. Genomics 11, 885–894 (1991).

    CAS  PubMed  Google Scholar 

  8. Guyer, M.S. & Collins, F.S. How is the Human Genome Project doing, and what have we learned so far? Proc. Natl. Acad. Sci. USA 92, 10841–10848 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ballabio, A. The rise and fall of positional cloning? Nature Genet. 3, 277–279 (1993).

    CAS  PubMed  Google Scholar 

  10. Tassabehji, M. et al. Waardenburg's syndrome patients have mutations in the human homologue of the Pax-3 paired box gene. Nature 355, 635–636 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Tassabehji, M., Newton, V.E. & Read, A.P. Waardenburg syndrome type 2 caused by mutations in the human microphtalmia (MITF) gene. Nature Genet. 8, 251–255 (1994).

    CAS  PubMed  Google Scholar 

  12. Gibson, F. et al. A type VII myosin encoded by the mouse deafness gene Shaker-1 . Nature 374, 62–64 (1995).

    CAS  PubMed  Google Scholar 

  13. Weil, D. et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374, 60–61 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Coyle, B. et al. Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4 . Nature Genet. 12, 421–423 (1996).

    CAS  PubMed  Google Scholar 

  15. Sheffield, V.C. et al. Pendred syndrome maps to chromosome 7q21–34 and is caused by an intrinsic defect in thyroid iodine organification. Nature Genet. 12, 424–426 (1996).

    CAS  PubMed  Google Scholar 

  16. Jin, H. et al. A novel X-linked gene, DDR shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Nature Genet. 14, 177–180 (1996).

    CAS  PubMed  Google Scholar 

  17. Wilson, P.J. et al. Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA. Proc. Natl. Acad. Sci. USA 87, 8531–8535 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Scott, H.S. et al. Human alpha-L-iduronidase: cDNA isolation and expression. Proc. Natl. Acad. Sci. USA 88, 9695–9699 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Baldwin, C.T., Hoth, C.F., Amos, J.A., da-Silva, E.O. & Milunsky, A. An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome. Nature 355, 637–638 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Barker, D.F. et al. Identification of mutations in the COL4A5 collagen gene in Alport syndrome. Science 248, 1224–1226 (1990).

    CAS  PubMed  Google Scholar 

  21. Hostikka, S.L. et al. Identification of a distinct type IV collagen α chain with restricted kidney distribution and assignment of its gene to the locus of X chromosome-linked Alport syndrome. Proc. Natl. Acad. Sci. USA 87, 1606–1610 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ahmad, N.N. et al. Stop codon in the procollagen II gene (COL2A1) in a family with the Stickler syndrome (arthro-ophthalmopathy). Proc. Natl. Acad. Sci. USA 88, 6624–6627 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Mochizuki, T. et al. Identification of mutations in the α3(IV) and α4(IV) collagen genes in autosomal recessive Alport syndrome. Nature Genet. 8, 77–81 (1994).

    CAS  PubMed  Google Scholar 

  24. Edery, P. et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome). Nature Genet. 12, 442–444 (1996).

    CAS  PubMed  Google Scholar 

  25. Hofstra, R.M.W. et al. A homozygous mutation in the endotheiin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet. 12, 445–447 (1996).

    CAS  PubMed  Google Scholar 

  26. Tremblay, P., Kessel, M. & Gruss, P. A transgenic neuroanatomical marker identifies cranial neural crest deficiencies associated with the Pax3 mutant Splotch. Dev. Biol. 171, 317–329 (1995).

    CAS  PubMed  Google Scholar 

  27. Baynash, A.G. et al. Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons. Cell 79, 1277–1285 (1994).

    CAS  PubMed  Google Scholar 

  28. Lahav, R., Ziller, C., Dupin, E. & Le Douarin, N. Endothelin-3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture. Proc. Natl. Acad. Sci. USA 93, 3892–3897 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hosoda, K. et al. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79, 1267–1276 (1994).

    CAS  PubMed  Google Scholar 

  30. Pavan, W.J. & Tilghman, S.M. Piebald lethal (s') acts early to disrupt the development of neural crest-derived melanocytes. Proc. Natl. Acad. Sci. USA 91, 7159–7163 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Motohashi, H., Hozawa, K., Oshima, T., Takeuchi, T. & Takasaka, T. Dysgenesis of melanocytes and cochlear dysfunction in mutant microphthalmia (mi) mice. Hearing Res. 80, 10–20 (1994).

    CAS  Google Scholar 

  32. Hemesath, T.J. et al. Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes Dev. 8, 2770–2780 (1994).

    CAS  PubMed  Google Scholar 

  33. Morreale de Escobar, G., Obregon, M.J. & Escobar del Rey, F. Fetal and maternal thyroid hormones. Hormone Res. 26, 12–27 (1987).

    CAS  PubMed  Google Scholar 

  34. Van Middlesworth, L. & Norris, C.H. Audiogenic seizures and cochlear damage in rats after perinatal antithyroid treatment. Endocrinology 106, 1686–1690 (1980).

    CAS  PubMed  Google Scholar 

  35. O'Malley, B.W., Jr., Li, D. & Turner, D.S. Hearing loss and cochlear abnormalities in the congenital hypothyroid (hyt/hyt) mouse. Hearing Res. 88, 181–189 (1995).

    Google Scholar 

  36. Takeda, K., Balzano, S., Sakurai, A., De Groot, L.J. & Refetoff, S. Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation. J. Clin. Invest. 87, 496–502 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bradley, D.J., Towle, H.C. & Young, W.S.R. Alpha and beta thyroid hormone receptor (TR) gene expression during auditory neurogenesis: evidence for TR isoform-specific transcriptional regulation in vivo . Proc. Natl. Acad. Sci. USA 91, 439–443 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Forrest, D., Erway, L.C., Ng, L., Altschuler, R. & Curran, T. Thyroid hormone receptor β is essential for development of auditory function. Nature Genet. 13, 354–357 (1996).

    CAS  PubMed  Google Scholar 

  39. Steel, K.P. & Smith, R.J.H. Normal hearing in Splotch (Sp/+) the mouse homologue of Waardenburg syndrome type 1. Nature Genet. 2, 75–79 (1992).

    CAS  PubMed  Google Scholar 

  40. Geissler, E.N., Ryan, M.A. & Housman, D.E. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell 55, 185–192 (1988).

    CAS  PubMed  Google Scholar 

  41. Flanagan, J.G., Chan, D.C. & Leder, P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell 64, 1025–1035 (1991).

    CAS  PubMed  Google Scholar 

  42. Bernex, F. et al. Spatial and temporal patterns of c-Kit-expressing cells in WlacZ/+ and wlacZ/WlacZ mouse embryos. Development 122, 3023–3033 (1996).

    CAS  PubMed  Google Scholar 

  43. EI-Amraoui, A. et al. Human Usher IB/mouse shaker-1; the retinal phenotype discrepancy explained by the presence/absence of myosin VIIA in the photoreceptor cells. Hum. Mol. Genet. 5 1171–1178 (1996).

    Google Scholar 

  44. Prezant, R.T., Shohat, M., Jabber, L., Pressman, S. & Fischel-Ghodsian, N. Biochemical characterization of a pedigree with mitochondrially inherited deafness. Am. J. Med. Genet. 44, 465–472 (1992).

    CAS  PubMed  Google Scholar 

  45. Reid, F.M., Vernham, G.A. & Jacobs, H.T. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum. Mutat. 3, 243–247 (1994).

    CAS  PubMed  Google Scholar 

  46. Morton, N.E. Genetic epidemiology of hearing impairment. in Genetics of Hearing Impairment 630, 16–31 (The New York Acad. Sci., New York, 1991).

    CAS  Google Scholar 

  47. Guilford, P. et al. A non-syndromic form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q. Nature Genet. 6, 24–28 (1994).

    CAS  PubMed  Google Scholar 

  48. Friedman, T.B. et al. A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nature Genet. 9, 86–91 (1995).

    CAS  PubMed  Google Scholar 

  49. Fukushima, K. et al. Consanguineous nuclear families used to identify a new locus for recessive non-syndromic hearing loss on 14q. Hum. Mol. Genet. 4, 1643–1648 (1995).

    CAS  PubMed  Google Scholar 

  50. Lander, E.S. & Botstein, D. Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236, 1567–1570 (1987).

    CAS  PubMed  Google Scholar 

  51. Coucke, P. et al. Linkage of autosomal dominant hearing loss to the short arm of chromosome 1 in two families. N. Engl. J. Med. 331, 425–431 (1994).

    CAS  PubMed  Google Scholar 

  52. de Kok, Y.J.M. et al. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4 . Science 267, 685–688 (1995).

    CAS  PubMed  Google Scholar 

  53. Steel, K.P. Inherited hearing defects in mice. Annu. Rev. Genet. 29, 675–701 (1995).

    CAS  PubMed  Google Scholar 

  54. Keats, B.J. et al. The deafness locus (dn) maps to mouse chromosome 19. Mamm. Genome 6, 8–10 (1995).

    CAS  PubMed  Google Scholar 

  55. Huygen, P.L., van Rijn, P.M., Cremers, C.W. & Theunissen, E.J. The vestibulo-ocular reflex in pupils at a Dutch school for the hearing impaired; findings relating to acquired causes. Int. J. Pediatr. Otorhinolaryngol. 25, 39–47 (1993).

    CAS  PubMed  Google Scholar 

  56. Nadeau, J.H., Kosowsky, M. & Steel, K.P. Comparative gene mapping, genome duplication, and the genetics of hearing. in Genetics of Hearing Impairment 630, 49–67 (The New York Acad. Sci., New York, 1991).

    Google Scholar 

  57. DeBry, R.W. & Seldin, M.F. Human/mouse homology relationships. Genomics 33, 337–351 (1996).

    CAS  PubMed  Google Scholar 

  58. Dryja, T.P. & Li, T. Molecular genetics of retinitis pigmentosa. Hum. Mol. Genet. 1739–1743 (1995).

    CAS  PubMed  Google Scholar 

  59. Fuchs, S. et al. A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nature Genet. 10, 360–362 (1995).

    CAS  PubMed  Google Scholar 

  60. Huang, S.H. et al. Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nature Genet. 11, 468–471 (1995).

    CAS  PubMed  Google Scholar 

  61. Robertson, N.G., Khetarpal, U., Gutierrez-Espeleta, G.A., Bieber, F.R. & Morton, C.C. Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening. Genomics 23, 42–50 (1994).

    CAS  PubMed  Google Scholar 

  62. Tilney, L.G., Tilney, M.S. & Guild, G.M. Factin bundles in Drosophila bristles. I. Two filament cross-links are involved in bundling. J. Cell Biol. 130, 629–638 (1995).

    CAS  PubMed  Google Scholar 

  63. Du, H., Gu, G., William, C.M. & Chalfie, M. Extracellular proteins needed for C. elegans mechanosensation. Neuron 16, 183–194 (1996).

    CAS  PubMed  Google Scholar 

  64. Bargmann, C.I. Molecular mechanisms of mechanosensation? Cell 78, 729–731 (1994).

    CAS  PubMed  Google Scholar 

  65. Gillespie, P.G., Wagner, M.C. & Hudspeth, A.J. Identification of a 120 kd hair-bundle myosin located near stereociliary tips. Neuron 11, 581–594 (1993).

    CAS  PubMed  Google Scholar 

  66. Avraham, K.B. et al. The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells. Nature Genet. 11, 369–375 (1995).

    CAS  PubMed  Google Scholar 

  67. Hasson, T., Heintzelman, M.B., Santos-Sacchi, J., Corey, D.R. & Mooseker, M.S. Expression in cochlea and retina of myosin Vila, the gene product defective in Usher syndrome type 1B. Proc. Natl. Acad. Sci. USA 92, 9815–9819 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Weil, D. et al. Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia. Proc. Natl. Acad. Sci. USA 93, 3232–3237 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Chaïb, H. et al. A gene responsible for a dominant form of neurosensory non-syndromic deafness maps to the NSRD1 recessive deafness gene interval. Hum. Mol. Genet. 3, 2219–2222 (1994).

    PubMed  Google Scholar 

  70. Guilford, P. et al. A human gene responsible for neurosensory, nonsyndromic recessive deafness is a candidate homologue of the mouse sh-1 gene. Hum. Mol. Genet. 3, 989–993 (1994).

    CAS  PubMed  Google Scholar 

  71. Tamagawa, Y. et al. A gene for a dominant form of non-syndromic sensorineural deafness (DFNA11) maps within the region containing the DFNB2 recessive deafness gene. Hum. Mol. Genet. 5, 849–852 (1996).

    CAS  PubMed  Google Scholar 

  72. Manolis, E.N. et al. A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12–13. Hum. Mol. Genet. 5, 1047–1050 (1996).

    CAS  PubMed  Google Scholar 

  73. Baldwin, C.T. Linkage of congenital, recessive deafness (DFNB4) to chromosome 7q31 and evidence for genetic heterogeneity in the Middle Eastern Druze population. Hum. Mol. Genet. 4, 1637–1642 (1995).

    CAS  PubMed  Google Scholar 

  74. Corey, D.P. & Breakefield, X.O. Transcription factors in inner ear development. Proc. Natl. Acad. Sci. USA 91, 433–436 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ernfors, P. Van de Water, T., Loring, J. & Jaenisch, R. Complementary roles of BDNF and NT-3 in vestibular and auditory development. Neuron 14, 1153–1164 (1995).

    CAS  PubMed  Google Scholar 

  76. Yamashita, H. & Oesterle, E.G. Induction of cell proliferation in mammalian inner-ear sensory epithelia by transforming growth factor alpha and epidermal growth factor. Proc. Natl. Acad. Sci. USA 92, 3152–3155 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Colvin, J.S., Bohne, B.A., Harding, G.W., McEwen, D.G. & Ornitz, D.M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).

    CAS  PubMed  Google Scholar 

  78. Markin, V.S. & Hudspeth, A.J. Gating-spring models of mechanoelectrical transduction by hair cells of the internal ear. Annu. Rev. Biophys. Biomol. Struct. 24, 59–83 (1995).

    CAS  PubMed  Google Scholar 

  79. Fukushima, K. et al. An autosomal recessive non-syndromic form of sensorineural hearing loss maps to 3p-DFNB6. Genome Res. 5, 305–308 (1995).

    CAS  PubMed  Google Scholar 

  80. Jain, R.K. et al. A human recessive neurosensory nonsyndromic hearing impairment locus is a potential homologue of the murine deafness (dn) locus. Hum. Mol. Genet. 4, 2391–2394 (1995).

    CAS  PubMed  Google Scholar 

  81. Veske, A. et al. Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan. Hum. Mol. Genet. 5, 165–168 (1996).

    CAS  PubMed  Google Scholar 

  82. Bonné-Tamir, B. et al. Linkage of congenital recessive deafness (gene DFNB10) to chromosome 21q22.3. Am. J. Hum. Genet. 58 1254–1259 (1996).

    PubMed  PubMed Central  Google Scholar 

  83. Chaïb, H. et al. A gene responsible for a sensorineural nonsyndromic recessive deafness maps to chromosome 2p22–23. Hum. Mol. Genet. 5, 155–158 (1996).

    PubMed  Google Scholar 

  84. Chaïb, H. et al. Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22. Hum. Mol. Genet. 5, 1061–1064 (1996).

    PubMed  Google Scholar 

  85. Chen, A.H. et al. Linkage of a gene for dominant non-syndromic deafness to chromosome 19. Hum. Mol. Genet. 4, 1073–1076 (1995).

    CAS  PubMed  Google Scholar 

  86. Van Camp, G. et al. Localization of a locus for non-syndromic hearing loss (DFNA5) to chromosome 7p. Hum. Mol. Genet. 4, 2159–2163 (1995).

    CAS  PubMed  Google Scholar 

  87. Lesperance, M.M. et al. A gene for autosomal dominant nonsyndromic hereditary hearing impairment maps to 4p16.3. Hum. Mol. Genet. 4, 1967–1972 (1995).

    CAS  PubMed  Google Scholar 

  88. Fagerheim, T. et al. Identification of a new locus for autosomal dominant nonsyndromic hearing impairment (DFNA7) in a large Norwegian family. Hum. Mol. Genet. 5, 1187–1191 (1996).

    CAS  PubMed  Google Scholar 

  89. Kirshhofer, K. et al. Localisation of a gene responsible for an autosomal dominant non-syndromic sensorineural hearing loss to chromosome 15. The Molecular Biology of Hearing and Deafness, Bethesda, USA, October 6–8 (1995).

  90. 0'Neill, M.E. et al. A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome 6. Hum. Mol. Genet. 5, 853–856 (1996).

    CAS  PubMed  Google Scholar 

  91. Bach, I. et al. Microdeletions in patients with gusher-associated, X-linked mixed deafness (DFN3). Am. J. Hum. Genet. 50, 38–44 (1992).

    Google Scholar 

  92. Lalwani, A.K. et al. A new nonsyndromic X-linked sensorineural hearing impairment linked to Xp21.2. Am. J. Hum. Genet. 55, 685–694 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. del Castillo, I. et al. A novel locus for non-syndromic sensorineural deafness (DFN6) maps to chromosome Xp22. Hum. Mol. Genet. 5, 1383–1387 (1996).

    CAS  PubMed  Google Scholar 

  94. Scott, D.A. et al. An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds. Am. J. Hum. Genet. 59, 385–391 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

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Petit, C. Genes responsible for human hereditary deafness: symphony of a thousand. Nat Genet 14, 385–391 (1996). https://doi.org/10.1038/ng1296-385

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