Alternative titles; symbols
ORPHA: 90641; DO: 0111734;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q13.31 | {Deafness, mitochondrial, modifier of} | 580000 | Mitochondrial | 3 | TRMU | 610230 |
A number sign (#) is used with this entry because aminoglycoside-induced deafness is associated with mutations in at least 2 mitochondrial-encoded genes, including MTRNR1 (561000) and MTCO1 (516030).
The mechanism of ototoxicity of aminoglycosides is thought to be interference with the production of ATP in the mitochondria of hair cells in the cochlea (Akiyoshoi et al., 1976). The aminoglycosides include kanamycin, gentamicin, tobramycin, and neomycin in addition to streptomycin.
Familial occurrence of streptomycin hearing loss, often with seemingly modest dosage of the antibiotic, was reported by Johnsonbaugh et al. (1974), Podvinec and Stefanovic (1966), Prazic and Salaj (1975), and Tsuiki and Murai (1971). The cases of Johnsonbaugh et al. (1974) involved mother and son.
Viljoen et al. (1983) described 8 persons with streptomycin ototoxicity in a large kindred of mixed ancestry from a remote rural area of South Africa. In each, severe permanent perceptive hearing loss developed during antituberculous therapy with streptomycin sulfate in conventional doses. The authors favored autosomal dominant inheritance.
Higashi (1989) reviewed published pedigrees in which 2 or more members had streptomycin-induced hearing loss and concluded that ordinary mendelian inheritance could not account for the findings. The disorder seemed to be transmitted almost exclusively through females. In only 2 of 28 families were there instances of affected father and children. Higashi (1989) favored mitochondrial inheritance.
Hu et al. (1991) analyzed 36 pedigrees in 1 district in Shanghai and showed that susceptibility to antibiotic ototoxicity was transmitted by females exclusively. An analysis of 18 other published pedigrees confirmed this conclusion, indicating that this disorder is mitochondrially determined. This situation is comparable to that in familial chloramphenicol toxicity (515000).
The mitochondrial ribosome in the cochlea is the most likely target of aminoglycoside ototoxicity, since the 'natural target' of aminoglycosides is the evolutionarily related bacterial ribosome. In bacterial studies, regions of the small ribosomal RNA appear to be important in translational fidelity. Thus, the mitochondrial rRNA genes, and especially the 12S rRNA gene (MTRNR1; 561000), were prime candidates for the site of the mtDNA mutation in maternally inherited aminoglycoside-induced deafness. In affected members of 3 families with maternally inherited aminoglycoside-induced deafness and in a large Israeli-Arab pedigree with possible combined autosomal and mitochondrial inheritance (see 221745), Prezant et al. (1993) identified a mutation in the 12S rRNA gene (1555A-G; 561000.0001).
Yuan et al. (2005) identified cosegregation of a mutation in the MTCO1 gene (7444G-A; 516030.0001) and a 1555A-G mutation in the MTRNR1 gene in 9 affected members of a 3-generation Chinese family with aminoglycoside-induced sensorineural hearing loss. One additional family member with both mutations, who had a history of exposure to noise but not to aminoglycoside, exhibited mild hearing impairment. The dose and age at the time of drug administration seemed to be correlated with the severity of the hearing loss.
Kalinec et al. (2005) demonstrated that supplementation of pregnant guinea pigs with L-carnitine prevented neonatal mortality and gentamicin-induced sensorineural hearing loss in their offspring. Experiments with auditory cell lines showed that gentamicin-induced toxicity was mediated by activation of the MAPK (176948) signaling pathway through upregulation of harakiri (HRK; 603447). L-carnitine prevented gentamicin-induced upregulation of Hrk and apoptosis via JNK1 (MAPK8; 601158). Studies with small interfering RNA (siRNA) showed that Hrk upregulation was necessary for gentamicin-induced apoptosis.
Akiyoshoi, M., Yano, S., Nakada, H., Sato, K., Shoji, T. Study on damage of the vestibular organs due to aminoglycoside antibiotics by means of supravital reduction of nitro-BT. Ear Res. Japan 7: 98-100, 1976.
Higashi, K. Unique inheritance of streptomycin-induced deafness. Clin. Genet. 35: 433-436, 1989. [PubMed: 2736791]
Hu, D.-N., Qui, W.-Q., Wu, B.-T., Fang, L.-Z., Zhou, F., Gu, Y.-P., Zhang, Q.-H., Yan, J.-H., Ding, Y.-Q., Wong, H. Genetic aspects of antibiotic induced deafness: mitochondrial inheritance. J. Med. Genet. 28: 79-83, 1991. [PubMed: 2002491] [Full Text: https://doi.org/10.1136/jmg.28.2.79]
Jaber, L., Shohat, M., Bu, X., Fischel-Ghodsian, N., Yang, H.-Y., Wang, S.-J., Rotter, J. I. Sensorineural deafness inherited as a tissue specific mitochondrial disorder. J. Med. Genet. 29: 86-90, 1992. [PubMed: 1613771] [Full Text: https://doi.org/10.1136/jmg.29.2.86]
Johnsonbaugh, R. E., Drexel, H. G., Light, I. J., Sutherland, J. M. Familial occurrence of drug-induced hearing loss. Am. J. Dis. Child. 127: 245-247, 1974. [PubMed: 4810278] [Full Text: https://doi.org/10.1001/archpedi.1974.02110210095014]
Kalinec, G. M., Fernandez-Zapico, M. E., Urrutia, R., Esteban-Cruciani, N., Chen. S., Kalinec, F. Pivotal role of harakiri in the induction and prevention of gentamicin-induced hearing loss. Proc. Nat. Acad. Sci. 102: 16019-16024, 2005. [PubMed: 16239342] [Full Text: https://doi.org/10.1073/pnas.0508053102]
Podvinec, S., Stefanovic, P. Surdite par la streptomycine et predisposition familiale. J. Franc. Otorhinolaryng. 15: 61-67, 1966.
Prazic, M., Salaj, B., Subotic, R. Familial sensitivity to streptomycin. J. Laryng. Otol. 78: 1037-1043, 1964. [PubMed: 14222845] [Full Text: https://doi.org/10.1017/s0022215100063131]
Prazic, M., Salaj, B. Ototoxicity with children caused by streptomycin. Audiology 14: 173-176, 1975. [PubMed: 1131123] [Full Text: https://doi.org/10.3109/00206097509071734]
Prezant, T. R., Agapian, J. V., Bohlman, M. C., Bu, X., Oztas, S., Qiu, W.-Q., Arnos, K. S., Cortopassi, G. A., Jaber, L., Rotter, J. I., Shohat, M., Fischel-Ghodsian, N. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4: 289-294, 1993. [PubMed: 7689389] [Full Text: https://doi.org/10.1038/ng0793-289]
Tsuiki, T., Murai, S. Familial incidence of streptomycin hearing loss and hereditary weakness of the cochlea. Audiology 10: 315-322, 1971. [PubMed: 4131355] [Full Text: https://doi.org/10.3109/00206097109072568]
Viljoen, D. L., Sellars, S. L., Beighton, P. Familial aggregation of streptomycin ototoxicity: autosomal dominant inheritance? J. Med. Genet. 20: 357-360, 1983. [PubMed: 6644766] [Full Text: https://doi.org/10.1136/jmg.20.5.357]
Yuan, H., Qian, Y., Xu, Y., Cao, J., Bai, L., Shen, W., Ji, F., Zhang, X., Kang, D., Mo, J. Q., Greinwald, J. H., Han, D., Zhai, S., Young, W.-Y., Guan, M.-X. 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. 138A: 133-140, 2005. [PubMed: 16152638] [Full Text: https://doi.org/10.1002/ajmg.a.30952]