Abstract
Hair cells are physiologically and structurally unique. However, the expression of the majority of macromolecules used for development and maintenance of their remarkable complexity appears to have been epigenetically hijacked from other functions during the evolution of the auditory system. The broad expression of many of these purloined genes should suggest caution when assuming that a particular mutated gene is causing simple isolated (nonsyndromic) hearing loss with no other medically significant features. Medically relevant issues accompanying hearing loss may be overlooked inadvertently. Narrowly focused medical history questions to be asked of study subjects and the selection of specific clinical tests often follow from knowledge of gene function in the various organ systems. These data are usually available only after deafness gene identification and the study of mouse models that recapitulate the inherited human deafness, and such studies may take several years. How many of the reported nonsyndromic deafness disorders are syndromic, in reality, remains to be determined. Early in a study of hereditary deafness, this can be an inherently difficult issue to resolve. Therefore, we suggest provisional classification of a specific human hereditary hearing loss as nonsyndromic only until there is adequate understanding of the normal function and expression pattern of a deafness gene that can then guide a focused clinical evaluation. This chapter examines these issues.
“It ain’t necessarily so” is a song about doubt in George and Ira Gershwin’s opera Porgy and Bess.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Bahmad, F., Merchant, S. N., Nadol, J. B., & Tranebjaerg, L. (2007). Otopathology in Mohr-Tranebjaerg syndrome. The Laryngoscope, 117, 1202–1208.
Ben-Yosef, T., Ness, S. L., Madeo, A. C., Bar-Lev, A., Wolfman, J. H., Ahmed, Z. M., Desnick, R. J., Willner, J. P., Avraham, K. B., Ostrer, H, Oddoux, C., Griffith, A. J., & Friedman, T. B. (2003). A mutation of PCDH15 among Ashkenazi Jews with the type 1 Usher syndrome. New England Journal of Medicine, 348, 1664–1670.
Bork J. M., Peters, L. M., Riazuddin, S., Bernstein, S., Ahmed, Z. M., Ness, S. L., Polomeno, R., Ramesh, A., Schloss, M., Srisailpathy, C. R. S., Wayne, S., Bellman, S., Desmukh, D., Der Kaloustian, V. M., Lalwani, A., Riazuddin, S., Bitner-Glindzicz, M., Nance, W., Liu X-Z., Wistow, G., Smith R. J. H., Griffith A. J., Wilcox, E., Friedman, T. B., & Morell, R. J. (2001). Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. The American Journal of Human Genetics, 68, 26–37.
Brownstein, Z., Ben-Yosef, T., Dagan, O., Frydman, M., Abeliovich, D., Sagi, M., Abraham, F. A., Taitelbaum-Swead, R., Shohat, M., Hildesheimer, M., Friedman, T. B., & Avraham K. B. (2004). The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa. Pediatric Research, 55, 995–1000.
Chaib, H., Place, C., Salem, N., Dode, C., Chardenoux, S., Weissenbach, J., el Zir, E., Loiselet, J., & Petit, C. (1996). Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22. Human Molecular Genetics, 5, 1061–1064.
Doherty, D., Chudley, A. E., Coghlan, G., Ishak, G. E., Innes, A. M., Lemire, E. G., Rogers, R. C., Mhanni, A. A., Phelps, I. G., Jones, S. J., Zhan, S. H., Fejes, A. P., Shahin, H., Kanaan, M., Akay, H., Tekin, M., Triggs-Raine, B., & Zelinski, T. (2012). GPSM2 mutations cause the brain malformations and hearing loss in Chudley-McCullough syndrome. American Journal of Human Genetics, 90, 1088–1093.
Engl, G., Florian, S., Tranebjaerg, L., & Rapaport, D. (2012). Alterations in expression levels of deafness dystonia protein 1 affect mitochondrial morphology. Human Molecular Genetics, 21, 287–299.
Friedman, T. B., Liang, Y., Weber, J. L., Hinnant, J. T., Barber, T. D., Winata, S., Arhya, I. N., & Asher, J. H., Jr. (1995). A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nature Genetics, 9, 86–91.
Griffith, A. J., & Friedman, T. B. (2014). Hereditary hearing loss. In J. B. Snow, Jr. & P. A. Wackym (Eds.), Ballenger’s otorhinolaryngology head and neck surgery, 18th ed. Beijing: People’s Medical Publishing House-USA.
Jenkinson, E. M., Rehman, A. U., Tom Walsh, T., Clayton-Smith, J., Lee K., Robert J., Morell R. J., Drummond M. C., Khan S. N., Naeem M. A., Rauf B., Billington N., Schultz J. M., Urquhart, J. E., Lee, M. K., Berry, A., Hanley, N. A., Mehta, S., Cilliers, D., Clayton, P. E., Kingston, H., Miriam, J.. Smith, M. J., Warner, T. T., Black, G. C., Trump, D., Davis, J. R. E., Ahmad, W., Leal, S. M., Riazuddin S., King, M-C., Friedman, T. B., & Newman, W. G. (2013). Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. The American Journal of Human Genetics, 92, 605–613.
Jin, H., May, M., Tranebjaerg, L., Kendall, E., Fontan, G., Jackson, J., Subramony, S. H., Arena, F., Lubs, H., Smith, S., Stevenson, R., Schwartz, C., & Vetrie, D. (1996). A novel X-linked gene, DDP, shows mutations in families with deafness (DFN-1), dystonia, mental deficiency and blindness. Nature Genetics, 14, 177–180.
Koehler, C. M., Leuenberger, D., Merchant, S., Renold, A., Junne, T.., & Schatz, G. (1999). Human deafness dystonia syndrome is a mitochondrial disease. Proceedings of the National Academy of Sciences of the USA, 96, 2141–2146.
Mohr, J., & Mageroy, K. (1960). Sex-linked deafness of a possibly new type. Acta Genetica et Statistica Medica, 10, 54–62.
Morell, R. J., Kim, H. J., Hood, L. J., Goforth, L., Friderici, K., Fisher, R., Van Camp, G., Berlin, C. I., Oddoux, C., Ostrer, H., Keats, B., & Friedman, T. B. (1998). Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. New England Journal of Medicine, 339, 1500–1505.
Nal, N., Ahmed, Z. M., Erkal, E., Alper, O. M., Luleci, G., Dinc, O., Waryah, A. M., Ain, Q., Tasneem, S., Husnain, T., Chattaraj, P., Riazuddin, S., Boger, E., Ghosh, M., Kabra, M., Morell, R. J., & Friedman, T. B. (2007). Mutational spectrum of MYO15A: The large N-terminal extension of myosin XVA is required for hearing. Human Mutation, 28, 1014–1019.
Pierce, S. B., Chisholm, K. M., Lynch, E. D., Lee, M. K., Walsh, T., Opitz, J. M., Li, W., Klevit, R. E., & King, M. C. (2011). Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proceedings of the National Academy of Sciences of the USA, 108, 6543–6548.
Probst, F. J., Fridell, R. A., Raphael, Y., Saunders, T. L., Wang, A., Liang, Y., Morell, R. J., Touchman, J. W., Lyons, R. H., Noben-Trauth, K., Friedman, T. B., & Camper, S. A. (1998). Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science, 280, 1444–1447.
Rehman, A. U., Gul, K., Morell, R. J., Lee, K., Ahmed, Z. M., Riazuddin, S., Ali, R. A., Shahzad, M., Jaleel, A. U., Andrade, P. B., Khan, S. N., Khan, S., Brewer, C. C., Ahmad, W., Leal, S. M., & Friedman, T. B. (2011). Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. Human Genetics, 130, 759–765.
Riazuddin, S., Castelein, C. M., Ahmed, Z. M., Lalwani, A. K., Mastroianni, M. A., Naz, S., Smith, T. N., Liburd, N. A., Friedman, T. B., Griffith, A. J., & Wilcox, E. R. (2000). Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nature Genetics, 26, 431–434.
Roesch, K.., Curran, S. P., Tranebjaerg, L., & Koehler, C. M. (2002). Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Human Molecular Genetics 11, 477–486.
Schultz, J. M., Yang, Y., Caride, A. J., Filoteo, A. G., Penheiter, A. R., Lagziel, A., Morell, R. J., Mohiddin, S. A., Fananapazir, L., Madeo, A. C., Penniston, J. T., & Griffith, A. J. (2005). Modification of human hearing loss by plasma-membrane calcium pump PMCA2. New England Journal of Medicine, 352, 1557–1564.
Schultz, J. M., Khan, S. N., Ahmed, Z. M., Riazuddin, S., Waryah, A. M., Chhatre, D., Starost, M. F., Ploplis, B., Buckley, S., Velasquez, D., Kabra, M., Lee, K., Hassan, M. J., Ali, G., Ansar, M., Ghosh, M., Wilcox, E. R., Ahmad, W., Merlino, G., Leal, S. M., Friedman, T. B., & Morell, R. J. (2009). Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. American Journal of Human Genetics, 85, 25–39.
Schultz, J. M., Bhatti, R., Madeo, A. C., Turriff, A., Muskett, J. A., Zalewski, C. K., King, K. A., Ahmed, Z. M., Riazuddin, S., Ahmad, N., Hussain, Z., Qasim, M., Kahn, S. N., Meltzer, M. R., Liu, X. Z., Munisamy, M., Ghosh, M., Rehm, H. L., Tsilou, E. T., Griffith, A. J., Zein, W. M., Brewer, C. C., & Friedman, T. B. (2011). Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes. Journal of Medical Genetics, 48, 767–775.
Shahin, H., Walsh, T., Rayyan, A. A., Lee, M. K., Higgins, J., Dickel, D., Lewis, K., Thompson, J., Baker, C., Nord, A. S., Stray, S., Gurwitz, D., Avraham, K. B., King, M. C., & Kanaan, M. (2010). Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families. European Journal of Human Genetics, 18, 407–413.
Swerdlow, R. H., & Wooten, G. F. (2001). A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome. Annals Neurology, 50, 537–540.
Tranebjaerg, L., Schwartz, C., Eriksen, H., Andreasson, S., Ponjavic, V., Dahl, A., Stevenson, R. E., May, M., Arena, F., & Barker, D. (1995). A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. Journal of Medical Genetics, 32, 257–263.
Walsh, T., Shahin, H., Elkan-Miller, T., Lee, M. K., Thornton, A. M., Roeb, W., Abu Rayyan, A., Loulus, S., Avraham, K. B., King, M-C., & Kanaan, M. (2010). Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82. American Journal of Human Genetics, 87, 90–94.
Wang, A., Liang, Y., Fridell, R. A., Probst, F. J., Wilcox, E. R., Touchman, J. W., Morton, C. C., Morell, R. J., Noben-Trauth, K., Camper, S. A., & Friedman, T. B. (1998). Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science, 280, 1447–1451.
Wayne, S.., Der Kaloustian, V. M., Schloss, M., Polomeno, R., Scott, D. A., Hejtmancik, J. F., Sheffield, V. C., & Smith, R. J. (1996). Localization of the Usher syndrome type ID gene (Ush1D) to chromosome 10. Human Molecular Genetics, 5, 1689–1692.
Yariz, K. O., Walsh, T., Akay, H., Duman, D., Akkaynak, A. C., King, M. C., & Tekin, M. (2012). A truncating mutation in GPSM2 is associated with recessive non-syndromic hearing loss. Clinical Genetics, 81, 289–293.
Acknowledgments
We thank Dennis Drayna, Andrew J. Griffith, and Julie Schultz for their comments and suggestions. SR is supported by Higher Education Commission, Islamabad, Pakistan. Intramural research fund DC000039-16 to TBF is from the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health, Bethesda, MD.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Friedman, T.B., Riazuddin, S. (2014). Nonsyndromic Deafness: It Ain’t Necessarily So. In: Popper, A., Fay, R. (eds) Perspectives on Auditory Research. Springer Handbook of Auditory Research, vol 50. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9102-6_9
Download citation
DOI: https://doi.org/10.1007/978-1-4614-9102-6_9
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-9101-9
Online ISBN: 978-1-4614-9102-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)