Abstract
Hearing impairment is a frequent condition, and genes have an important role in its etiology. The majority of hearing loss occurs in non-syndromic form, with deafness being the only clinically recognizable feature. More than 60 nuclear genes or loci have been shown to be involved in non-syndromic hearing loss, but mutations in mitochondrial DNA also cause hearing impairment. Mitochondrial DNA mutations usually lead to progressive hearing loss with an age of onset varying from childhood to early adulthood. It is interesting to note that there is a great variability among phenotypes between individuals harboring the same mitochondrial mutation, even within the same family, and the phenotype may range from profound deafness to completely normal hearing. In the past years, the debate on mitochondrial mutations has been about the penetrance, the tissue specificity and the mechanisms of modifier genes that can modulate the severity of the phenotypic expression of the deafness-associated mitochondrial DNA mutations. Here we summarize evidence regarding modifying genes, and we discuss the effect of the coexistence of mitochondrial and GJB2 mutations in families reported to date.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Davis, A. C. The prevalence of hearing impairment and reported hearing disability among adults in Great Britain. Int. J. Epidemiol. 18, 911–917 (1989).
Marazita, M. L., Ploughman, L. M., Rawlings, B., Remington, E., Arnos, K. S. & Nance, W. E. Genetic epidemiological studies of early-onset deafness in the U.S. school-age population. Am. J. Med. Genet. 46, 486–491 (1993).
Jacobs, H. T., Hutchin, T. P., Käppi, T., Gillies, G., Minkkinen, K., Walker, J. et al. Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment. Eur. J. Hum. Genet. 13, 26–33 (2005).
Giles, R. E., Blanc, H., Cann, H. M. & Wallace, D. C. Maternal inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA. 77, 6715–6719 (1980).
Dimauro, S. & Davidzon, G. Mitochondrial DNA and disease. Ann. Med. 37, 222–232 (2005).
Sudoyo, H., Suryadi, H., Lertrit, P., Pramoonjago, P., Lyrawati, D. & Marzuki, S. Asian-specific mtDNA backgrounds associated with the primary G11778A mutation of Leber's hereditary optic neuropathy. J. Hum. Genet. 47, 594–604 (2002).
Guan, M. X., Fischel-Ghodsian, N. & Attardi, G. Nuclear background determines biochemical phenotype in the deafness-associated mitochondrial 12S rRNA mutation. Hum. Mol. Genet. 10, 573–580 (2001).
Kokotas, H., Petersen, M. B. & Willems, P. J. Mitochondrial deafness. Clin. Genet. 71, 379–391 (2007).
Linnane, A. W., Marzuki, S., Ozawa, T. & Tanaka, M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1, 642–645 (1989).
de Grey, A. D. Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation. Rejuvenation Res. 8, 13–17 (2005).
Estivill, X., Govea, N., Barceló, E., Badenas, C., Romero, E., Moral, L. et al. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am. J. Hum. Genet. 62, 27–35 (1998).
Li, R., Xing, G., Yan, M., Cao, X., Liu, X. Z., Bu, X. et al. Cosegregation of C-insertion at position 961 with the A1555G mutation of the mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss. Am. J. Med. Genet. A 124, 113–117 (2004).
Matthijs, G., Claes, S., Longo-Mbenza, B. & Cassiman, J. J. Non-syndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairean pedigree. Eur. J. Hum. Genet. 4, 46–51 (1996).
Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Oztas, S., Qiu, W. Q. et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat. Genet. 4, 289–294 (1993).
Zhao, H., Li, R., Wang, Q., Yan, Q., Deng, J. H., Han, D. et al. Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Am. J. Hum. Genet. 74, 139–152 (2004).
Pandya, A., Xia, X., Radnaabazar, J., Batsuuri, J., Dangaansuren, B., Fischel-Ghodsian, N. et al. Mutation in the mitochondrial 12S rRNA gene in two families from Mongolia with matrilineal aminoglycoside ototoxicity. J. Med. Genet. 34, 169–172 (1997).
López-Bigas, N., Rabionet, R., Martinez, E., Bravo, O., Girons, J., Borragan, A. et al. Mutations in the mitochondrial tRNA Ser(UCN) and in the GJB2 (connexin 26) gene are not modifiers of the age at onset or severity of hearing loss in Spanish patients with the 12S rRNA A1555G mutation. Am. J. Hum.Genet. 66, 1465–1467 (2000).
Chu, S. Y., Chiang, S. C., Chien, Y. H. & Hwu, W. L. Screening of mitochondrial DNA mutations in subjects with non-syndromic familial hearing impairment in Taiwan. Acta. Paediatr. Taiwan 43, 330–333 (2002).
Yuan, H., Qian, Y., Xu, Y., Cao, J., Bai, L., Shen, W. et al. Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. Am. J. Med. Genet. 138, 133–140 (2005).
Zhu, Y., Qian, Y., Tang, X., Wang, J., Yang, L., Liao, Z. et al. Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNASer(UCN) genes in two Chinese families. Biochem. Biophys. Res. Commun. 342, 843–850 (2006).
Abreu-Silva, R. S., Lezirovitz, K., Braga, M. C., Spinelli, M., Pirana, S., Della-Rosa, V. A. et al. Prevalence of the A1555G (12S rRNA) and tRNASer(UCN) mitochondrial mutations in hearing-impaired Brazilian patients. Braz. J. Med. Biol. Res. 39, 219–226 (2006).
Yuan, H., Chen, J., Liu, X., Cheng, J., Wang, X., Yang, L. et al. Coexistence of mitochondrial 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigrees with aminoglycoside-induced and non-syndromic hearing loss. Biochem. Biophys. Res. Commun. 362, 94–100 (2007).
Jin, L., Yang, A., Zhu, Y., Zhao, J., Wang, X., Yang, L. et al. Mitochondrial tRNASer(UCN) gene is the hot spot for mutations associated with aminoglycoside-induced and non-syndromic hearing loss. Biochem. Biophys. Res. Commun. 361, 133–139 (2007).
Rydzanicz, M., Wróbel, M., Cywiñska, K., Froehlich, D., Gawecki, W., Szyfter, W. et al. Screening of the general Polish population for deafness-associated mutations in mitochondrial 12S rRNA and tRNA Ser(UCN) genes. Genet. Test Mol. Biomarkers 13, 167–172 (2009).
Hernandez, V. H., Bortolozzi, M., Pertegato, V., Beltramello, M., Giarin, M., Zaccolo, M. et al. Unitary permeability of gap junction channels to second messengers measured by FRET microscopy. Nat. Methods 4, 353–358 (2007).
Rabionet, R., Gasparini, P. & Estivill, X. Molecular genetics of hearing impairment due to mutations in gap junction genes encoding beta connexins. Hum. Mutat. 16, 190–202 (2000).
Richard, G., Rouan, F., Willoughby, C. E., Brown, N., Chung, P., Ryynänen, M. et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am. J. Hum. Genet. 70, 1341–1348 (2002).
Ballana, E., Ventayol, M., Rabionet, R., Gasparini, P., Estivill, X. Connexins and deafness homepage, http://davinci.crg.es/deafness/.
Petersen, M. B. & Willems, P. J. Non-syndromic, autosomal-recessive deafness. Clin. Genet. 69, 371–392 (2006).
Denoyelle, F., Marlin, S., Weil, D., Moatti, L., Chauvin, P., Garabédian, E. N. et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet 353, 1298–1303 (1999).
Cohn, E. S., Kelley, P. M., Fowler, T. W., Gorga, M. P., Lefkowitz, D. M., Kuehn, H. J. et al. Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). Pediatrics 103, 546–550 (1999).
Kokotas, H., Theodosiou, M., Korres, G., Grigoriadou, M., Ferekidou, E., Giannoulia-Karantana, A. et al. Sudden hearing loss in a family with GJB2 related progressive deafness. Int. J. Pediatr. Otorhinolaryngol. 72, 1735–1740 (2008).
Torroni, A., Cruciani, F., Rengo, C., Sellitto, D., López-Bigas, N., Rabionet, R. et al. The A1555G mutation in the 12S rRNA gene of human mtDNA: recurrent origins and founder events in families affected by sensorineural deafness. Am. J. Hum. Genet. 65, 1349–1358 (1999).
Abe, S., Kelley, P. M., Kimberling, W. J. & Usami, S. I. Connexin 26 gene (GJB2) mutation modulates the severity of hearing loss associated with the 1555A → G mitochondrial mutation. Am. J. Med. Genet. 103, 334–338 (2001).
Kokotas, H., Grigoriadou, M., Korres, G. S., Ferekidou, E., Papadopoulou, E., Neou, P. et al. The A1555G mitochondrial DNA mutation in Greek patients with non-syndromic, sensorineural hearing loss. Biochem. Biophys. Res. Commun. 390, 755–757 (2009).
Fischel-Ghodsian, N. Mitochondrial mutations and hearing loss: paradigm for mitochondrial genetics. Am. J. Hum. Genet. 62, 15–19 (1998).
Brummett, R. E., Fox, K. E., Bendrick, T. W. & Himes, D. L. Ototoxicity of tobramycin, gentamicin, amikacin and sisomicin in the guinea pig. J. Antimicrob. Chemother. 4 (Suppl.), 73–83 (1978).
Brummett, R. E. & Morrison, R. B. The incidence of aminoglycoside antibiotic-induced hearing loss. Arch. Otolaryngol. Head Neck Surg. 116, 406–410 (1990).
Schacht, J. Biochemical basis of aminoglycoside ototoxicity. Otolaryngol. Clin. North Am. 26, 845–856 (1993).
Lim, D. J. Effects of noise and ototoxic drugs at the cellular level in the cochlea: a review. Am. J. Otolaryngol. 7, 73–99 (1986).
Lu, J., Qian, Y., Li, Z., Yang, A., Zhu, Y., Li, R. et al. Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation. Mitochondrion 10, 69–81 (2010).
Bykhovskaya, Y., Mengesha, E., Wang, D., Yang, H., Estivill, X., Shohat, M. et al. Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation. Mol. Genet. Metab. 82, 27–32 (2004).
Seidel-Rogol, B. L., McCulloch, V. & Shadel, G. S. Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop. Nat. Genet. 33, 23–24 (2003).
Li, X., Li, R., Lin, X. & Guan, M. X. Isolation and characterization of the putative nuclear modifier gene MTO1 involved in the pathogenesis of deafness-associated mitochondrial 12 S rRNA A1555G mutation. J. Biol. Chem. 277, 27256–27264 (2002).
Li, X. & Guan, M. X. A human mitochondrial GTP binding protein related to tRNA modification may modulate phenotypic expression of the deafness-associated mitochondrial 12S rRNA mutation. Mol. Cell Biol. 22, 7701–7711 (2002).
Guan, M. X., Yan, Q., Li, X., Bykhovskaya, Y., Gallo-Teran, J., Hajek, P. et al. Mutation in TRMU related to transfer RNA modification modulates the phenotypic expression of the deafness-associated mitochondrial 12S ribosomal RNA mutations. Am. J. Hum. Genet. 79, 291–302 (2006).
del Castillo, F. J., Rodríguez-Ballesteros, M., Martín, Y., Arellano, B., Gallo-Terán, J., Morales-Angulo, C. et al. Heteroplasmy for the 1555A>G mutation in the mitochondrial 12S rRNA gene in six Spanish families with non-syndromic hearing loss. J. Med. Genet. 40, 632–636 (2003).
Lu, S. Y., Nishio, S., Tsukada, K., Oguchi, T., Kobayashi, K., Abe, S. et al. Factors that affect hearing level in individuals with the mitochondrial 1555A>G mutation. Clin. Genet. 75, 480–484 (2009).
Guan, M. X., Fischel-Ghodsian, N. & Attardi, G. Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation. Hum. Mol. Genet. 5, 963–971 (1996).
Zhao, H., Young, W. Y., Yan, Q., Li, R., Cao, J., Wang, Q. et al. Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res. 33, 1132–1139 (2005).
Acknowledgements
This study was supported in part by a grant from Oticon Fonden, Denmark (MBP).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kokotas, H., Grigoriadou, M., Korres, G. et al. Are GJB2 mutations an aggravating factor in the phenotypic expression of mitochondrial non-syndromic deafness?. J Hum Genet 55, 265–269 (2010). https://doi.org/10.1038/jhg.2010.23
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2010.23
