ORPHA: 90641; DO: 0111751;
A number sign (#) is used with this entry because mitochondrially inherited nonsyndromic sensorineural deafness can be caused by mutation in any 1 of several mitochondrial genes, including MTRNR1 (561000), MTTS1 (590080), MTCO1 (516030), MTTH (590040), MTND1 (516000), and MTTI (590045).
See also aminoglycoside-induced deafness (580000), which can also be caused by mutation in mitochondrial genes.
Mutations in mitochondrial DNA (mtDNA) have been found to be associated with nonsyndromic sensorineural hearing loss. Matrilineal relatives within and among families carrying certain pathogenic mitochondrial mutations exhibit a wide range of penetrance, severity, and age of onset of hearing loss, indicating that the mitochondrial mutations by themselves are not sufficient to produce a deafness phenotype. Modifier factors, such as nuclear and mitochondrial genes, or environmental factors, such as exposure to aminoglycosides, appear to modulate the phenotypic manifestations (summary by Tang et al., 2007).
Prezant et al. (1993) reported a large Arab Israeli kindred segregating nonsyndromic deafness following maternal inheritance.
Reid et al. (1994) reported a Scottish pedigree with maternal inheritance of progressive, postlingual, sensorineural hearing loss involving high frequencies.
Friedman et al. (1999) studied a large African American kindred with typical maternally inherited nonsyndromic hearing loss. Clinical examination of several members of the kindred showed a normal general state of health, but in 14 of the members tested, variable degrees of sensorineural hearing loss were noted. In the pedigree, 34 of 38 offspring of deaf mothers had hearing impairment, but none of 22 offspring of deaf fathers had hearing impairment.
Xing et al. (2006) reported a large Chinese family with early-onset nonsyndromic profound sensorineural hearing loss showing maternal inheritance. There was incomplete penetrance (43.5%).
Bravo et al. (2006) reported 18 individuals from 9 Spanish families with mitochondrial nonsyndromic hearing loss. The phenotype ranged from mild to profound deafness and was most severe at high frequencies. All 18 affected and 6 unaffected individuals were found to carry the 1555A-G mutation in the MTNRN1 gene (561000.0001). In affected individuals, the age at onset ranged from 1 to 20 years. Four individuals with moderate to profound hearing loss had aminoglycoside-induced deafness. Tinnitus was reported by 9 deaf and 2 nonaffected individuals, and 2 deaf individuals reported dizziness. All with deafness had absent otoacoustic emissions with normal auditory brainstem responses, suggesting dysfunction of the outer hair cells of the cochlea. Two normal hearing individuals had subclinical alterations of the acoustic reflexes at high frequencies. Bravo et al. (2006) stated that the findings were consistent with a model in which a defect in mitochondrial translation of ribosomes results in a decline of ATP production and an increase in reactive oxygen species (ROS), resulting in hair cell apoptosis.
Tang et al. (2007) reported 7 Han Chinese families with aminoglycoside-induced and nonsyndromic bilateral hearing loss due to the 1555A-G mutation. The penetrance of hearing loss in these pedigrees ranged from 3 to 29%, with an average of 13.6%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss ranged from 0 to 17%, with an average of 5.3%. Haplotype analysis suggested that the 1555A-G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. Tang et al. (2007) concluded that aminoglycoside exposure appears to be a major modifier factor for the phenotypic manifestation of the 1555A-G mutation in these Chinese families.
Yan et al. (2011) reported a large 5-generation Han Chinese family with maternally inherited nonsyndromic adult-onset hearing loss. There was wide variability in age at onset and severity, but the average age at onset was 29 years. Genetic analysis identified a heteroplasmic 12201T-C transition in the MTTH gene (590040.0004). The severity correlated with mutation load. Lymphoblastoid cell lines from 3 mutation carriers showed decreased levels of MTTH mRNA (about 25% of normal) as well as about 50% reduction in mitochondrial translation products compared to controls. Overall oxygen consumption of these cells was about 65% of normal, indicating defective respiration.
In affected members of a large Arab Israeli kindred with nonsyndromic deafness, Prezant et al. (1993) found a 1555A-G transition in the 12S rRNA gene (MTRNR1) (561000.0001). In 138 unrelated Japanese patients with nonsyndromic hearing loss, Noguchi et al. (2004) identified the 1555A-G mutation in 1 (1.6%) of 63 sporadic patients and 6 (8.0%) of 75 familial patients.
In a Scottish pedigree with sensorineural hearing loss, Reid et al. (1994) identified a mutation in the MTTS1 gene (7445A-G; 590080.0002). Hutchin et al. (2001) described a 3-generation family from Ukraine with nonsyndromic sensorineural progressive deafness due to a homoplasmic 7445A-G mutation in the MTTS1 gene. The authors stated that all 4 reported families with this mutation have been of different ethnic backgrounds, suggesting that the mutation arose on 4 independent genetic backgrounds. In a large African American family with typical maternally inherited nonsyndromic hearing loss previously reported by Friedman et al. (1999), Sue et al. (1999) identified a homoplasmic 7511T-C transition in the MTTS1 gene (590080.0005).
Pandya et al. (1999) reported 6 unrelated Mongolian deaf students with cosegregation of a homoplasmic 1555A-G mutation and a homoplasmic 7444G-A mutation in the MTCO1 gene (516030.0001). Five of the individuals had a family history consistent with matrilineal transmission of hearing loss. Only 2 individuals had a definite history of aminoglycoside exposure, but all 6 had severe to profound bilateral sensorineural hearing loss detected at birth or in infancy.
Xing et al. (2006) reported a large Chinese family with early-onset nonsyndromic profound sensorineural hearing loss and identified a homoplasmic mutation in the MTRNR1 gene (827G-A; 561000.0007) in affected individuals. Chaig et al. (2008) reported a large Argentinian family with nonsyndromic sensorineural hearing loss both with and without aminoglycoside exposure and identified a homoplasmic MTRNR1 827G-A mutation.
Bravo, O., Ballana, E., Estivill, X. Cochlear alterations in deaf and unaffected subjects carrying the deafness-associated A1555G mutation in the mitochondrial 12S rRNA gene. Biochem. Biophys. Res. Commun. 344: 511-516, 2006. [PubMed: 16631122] [Full Text: https://doi.org/10.1016/j.bbrc.2006.03.143]
Chaig, M. R., Zernotti, M. E., Soria, N. W., Romero, O. F., Romero, M. F., Gerez, N. M. A mutation in mitochondrial 12S rRNA, A827G, in Argentinean family with hearing loss after aminoglycoside treatment. Biochem. Biophys. Res. Commun. 368: 631-636, 2008. [PubMed: 18261986] [Full Text: https://doi.org/10.1016/j.bbrc.2008.01.143]
Friedman, R. A., Bykhovskaya, Y., Sue, C. M., DiMauro, S., Bradley, R., Fallis-Cunningham, R., Paradies, N., Pensak, M. L., Smith, R. J., Groden, J., Li, X. C., Fischel-Ghodsian, N. Maternally inherited nonsyndromic hearing loss. Am. J. Med. Genet. 84: 369-372, 1999. [PubMed: 10340654] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990604)84:4<369::aid-ajmg12>3.0.co;2-v]
Hutchin, T. P., Lench, N. J., Arbuzova, S., Markham, A. F., Mueller, R. F. Maternally inherited hearing impairment in a family with the mitochondrial DNA A7445G mutation. Europ. J. Hum. Genet. 9: 56-58, 2001. [PubMed: 11175301] [Full Text: https://doi.org/10.1038/sj.ejhg.5200581]
Noguchi, Y., Yashima, T., Ito, T., Sumi, T., Tsuzuku, T., Kitamura, K. Audiovestibular findings in patients with mitochondrial A1555G mutation. Laryngoscope 114: 344-348, 2004. [PubMed: 14755216] [Full Text: https://doi.org/10.1097/00005537-200402000-00031]
Pandya, A., Xia, X.-J., Erdenetungalag, R., Amendola, M., Landa, B., Radnaabazar, J., Dangaasuren, B., Van Tuyle, G., Nance, W. E. Heterozygous point mutations in the mitochondrial tRNA Ser(UCN) precursor coexisting with the A1555G mutation in deaf students from Mongolia. (Letter) Am. J. Hum. Genet. 65: 1803-1806, 1999. [PubMed: 10577941] [Full Text: https://doi.org/10.1086/302658]
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]
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. [PubMed: 8019558] [Full Text: https://doi.org/10.1002/humu.1380030311]
Sue, C. M., Tanji, K., Hadjigeorgiou, G., Andreu, A. L., Nishino, I., Krishna, S., Bruno, C., Hirano, M., Shanske, S., Bonilla, E., Fischel-Ghodsian, N., DiMauro, S., Friedman, R. Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN)) gene. Neurology 52: 1905-1908, 1999. [PubMed: 10371545] [Full Text: https://doi.org/10.1212/wnl.52.9.1905]
Tang, X., Yang, L., Zhu, Y., Liao, Z., Wang, J., Qian, Y., Tao, Z., Hu, L., Wu, G., Lan, J., Wang, X., Ji, J., Wu, J., Ji, Y., Feng, J., Chen, J., Li, Z., Zhang, X., Lu, J., Guan, M.-X. Very low penetrance of hearing loss in seven Han Chinese pedigrees carrying the deafness-associated 12S rRNA A1555G mutation. Gene 393: 11-19, 2007. [PubMed: 17341440] [Full Text: https://doi.org/10.1016/j.gene.2007.01.001]
Xing, G., Chen, Z., Wei, Q., Tian, H., Li, X., Zhou, A., Bu, X., Cao, X. Maternally inherited non-syndromic hearing loss associated with Xing, G.; Chen, Z.; Wei, Q.; Tian, H.; Li, X.; Zhou, A.; Bu, X.; Cao, X.: Maternally inherited non-syndromic hearing loss associated with mitochondrial 12S rRNA A827G mutation in a Chinese family. Biochem. Biophys. Res. Commun. 344: 1253-1257, 2006. [PubMed: 16650816] [Full Text: https://doi.org/10.1016/j.bbrc.2006.04.033]
Yan, X., Wang, X., Wang, Z., Sun, S., Chen, G., He, Y., Mo, J. Q., Li, R., Jiang, P., Lin, Q., Sun, M., Li, W., Bai, Y., Zhang, J., Zhu, Y., Lu, J., Yan, Q., Li, H., Guan, M.-X. Maternally transmitted late-onset non-syndromic deafness is associated with the novel heteroplasmic T12201C mutation in the mitochondrial tRNA-His gene. J. Med. Genet. 48: 682-690, 2011. [PubMed: 21931169] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100219]