Mitochondrial Deafness

Abstract

The last decade has led to the identification of several mitochondrial DNA mutations associated with hearing loss. Since the only known function of the human mitochondrial chromosome is to participate in the production of chemical energy through oxidative phosphorylation, it was not unexpected that mitochondrial mutations interfering with energy production could cause systemic neuromuscular disorders, which have as one of their features hearing impairment. Surprisingly, however, inherited mitochondrial mutations also have been found to be a cause of non-syndromic hearing loss, and predispose to aminoglycoside induced hearing loss, while acquired mitochondrial mutations have been proposed as one of the causes of presbycusis. After a brief review of mitochondrial genetics, we will outline the different mitochondrial mutations associated with hearing loss, describe the audiological features, and discuss the clinical relevance of diagnosing these mutations. Clinical expression of these mitochondrial mutations is dependent on environmental exposures and nuclear-encoded modifier genes. Preventive and therapeutic strategies will depend on identification and avoidance of the environmental exposures, and the identification of the nuclear-encoded modifier genes. Experimental approaches to identify these modifier genes will be presented.

Mitochondrial ribosomal proteins: Candidate genes for mitochondrial disease

“…11 This finding was confirmed subsequently in multiple populations around the world. 13 It appears that the mitochondrial dysfunction induced by the A1555G mutation is primarily a decrease in mitochondrial protein synthesis affecting all proteins similarly. 14 Importantly, the percentage decrease of protein synthesis when compared to ethnically matched cell lines without the mtDNA mutation varies with the clinical status of the individual who provided the cell line.…”

“…Nonsyndromic deafness was initially identified in a large Arab-Israeli pedigree, and subsequently confirmed in populations around the world with the highest recognized frequency in Spain. [11][12][13] Aminoglycoside ototoxicity is one of the most common causes of acquired deafness. Although vestibulocochlear damage is nearly universal when high drug levels are present for prolonged periods, at lower drug levels there appears to be a significant genetic component influencing susceptibility to aminoglycoside ototoxicity.…”

Detection of Deafness-Causing Mutations in the Greek Mitochondrial Genome

“…Hearing loss can also be non-genetic in origin, induced by factors such as ototoxic drugs, perinatal infections, traumas etc. However, many cases are multifactorial, involving a collaboration of exogenous factors and mutations in single genes or several genes [5,6]. The severity of hearing loss may range from mild to profound and the damage in hearing may include all frequencies [6].…”

Prevention and modulation of aminoglycoside ototoxicity (Review)

“…A1555G is expected to be the most prevalent deafnesslinked mitochondrial mutation worldwide, having been identified in both Caucasians and Asians as part of different, unrelated haplogroups (21,23,24). It appears that the mutation is more frequent in Asian populations (32), as the majority of episodes of ototoxicity have been described in Chinese and other Asian patients.…”

“…21,22). The most representative deafness-linked mitochondrial mutations -at the level of five distinct genes -are: i) A7445G (segregating with palmoplantar keratoderma in some individuals), 7472insC (associated with ataxia and/or focal myoclonus in some individuals), T7510C and T7511C, located in or adjacent to the tRNA Ser(UCN) gene; ii) A3243G, in the tRNA leu(UUR) gene (can be associated with diabetes mellitus; 23,24); iii) A8344G, in the tRNA lys gene; iv) T8993G, in the ATPase 6 gene; v) A827G, 961insC, 961delT/T961G (both associated in some cases with aminoglycoside ototoxicity), T1005C, T1095C, A1116G, T1291C, C1494T and A1555G, in the gene encoding the 12S rRNA (25)(26)(27)(28)(29).…”