Учебники / Genetics and Auditory Disorders Keats 2002

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7. Mitochondrial DNA Mutations 229

bling a functional mitochondrial protein-synthesizing system. The proteins are formed by translation of 13 mRNAs on mitochondrion-specific ribosomes, using a mitochondrion-specific genetic code. These proteins interact with approximately sixty nuclear-encoded proteins to form the five enzyme complexes required for oxidative phosphorylation. These complexes are bound to the mitochondrial inner membrane, and are involved in electron transport and ATP synthesis (reviewed in Attardi and Schatz 1988).

Mitochondrial DNA is transmitted exclusively through mothers. This leads to the expectation that a defect in a mitochondrial gene should lead to disease equally in both sexes, but can only be transmitted through the maternal line. Normally, most healthy individuals appear to have only a single mtDNA genotype (known as homoplasmy). However, in many mitochondrial disease states the mtDNA population is mixed (heteroplasmic), with both the normal and mutant genotypes present (Wallace 1992). The amount of heteroplasmy varies from tissue to tissue, and for cells within a tissue, and the severity of the symptoms does not always correlate well with the proportion of mutant mtDNAs. While for most of the multisystemic mitochondrial syndromes the homoplasmic state would presumably be lethal, mutant mtDNA homoplasmy is observed for two tissue-specific diseases, the ocular disorder Leber’s hereditary optic neuroretinopathy (Howell 1994) and maternally inherited hearing loss.

3. Hearing Impairment Due to Mitochondrial DNA Mutations

Hearing loss can be due to both inherited and acquired, as well as heteroplasmic and homoplasmic, mtDNA mutations. These data have recently been reviewed (Fischel-Ghodsian, 1998a and b), and are summarized with the inclusion of the most recent data in Table 7.1.

3.1 Mitochondrial Mutations and Syndromic

Hearing Loss

Systemic neuromuscular syndromes such as Kearns-Sayre syndrome, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), and mitochondrial encephalomyopathy with ragged red fibers (MERRF), have hearing loss frequently as one of their clinical signs (Schon et al. 1997; Chomyn 1998; Sue et al. 1998). In these cases, the heteroplasmic mutation can be found generally at highest levels in nerves and muscle. Because of the higher energy requirements of muscle and nervous tissue, and the fact that small numbers of dysfunctional muscle and nerve cells can interrupt the function of many neighboring normal cells, mtDNA mutations in those tissues are thought to be particularly harmful. It is not unexpected