Biology Reference
In-Depth Information
bling a functional mitochondrial protein-synthesizing system. The proteins
are formed by translation of 13 mRNAs on mitochondrion-specific ribo-
somes, 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 mito-
chondrial 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 hetero-
plasmic 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 heteroplas-
mic 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
