Biology Reference
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encoded by the mitochondrial genome (Table 7.1). This situation should be
contrasted with other mitochondrial disorders such as Leber's hereditary
optic neuroretinopathy and Leigh's syndrome, in which missense mutations
are the rule (MITOMAP, 1995).
(2) Biochemical analysis of the effect of these mutations demonstrates a
RNA processing defect or a decrease in translational efficiency. While the
effect of these mutations has not been studied in the cochlea, analysis of
lymphoblastoid cell lines has given support to the idea that the mutations
affect RNA processing or translation. The A1555G mutation in the
12S
ribosomal RNA gene, which is part of the mitochondrial ribosome, causes
a generalized decrease in mitochondrial protein synthesis (Guan et al.
1996). The A7445G mutation causes a processing defect of the light strand
of the polycistronic mRNA, leading to a 70% reduction in
tRNASer(UCN)
and
ND6
mRNA, which is cotranscribed with the
tRNASer(UCN)
.The
decrease in the tRNA leads to a general decrease in protein synthesis, which
is exacerbated for
ND6
by the decrease of the mRNA for this protein
(Guan et al. 1998). The Cins7472 mutation has not been biochemically ana-
lyzed in detail, but involves a nucleotide deletion in the TxC loop of the
same
tRNASer(UCN)
that the A7445G mutation affects (Tiranti et al. 1995;
Verhoeven et al. 1998). The main mitochondrial mutation associated with
syndromic hearing loss, the A3243G mutation in the
tRNALeu(UUR)
gene,
has been proposed to interfere with transcription termination (Hess et al.
1991), although the precise mechanism of the pathogenicity of this muta-
tion remains unclear (Moraes et al. 1992; Flierl et al. 1997).
(3) In humans and other organisms, tissue-specific isoenzymes and splice
variants of genes involved in general cellular processes, also called house-
keeping genes, have been described. For example, tissue-specific isoen-
zymes have been identified for some of the nuclear-encoded subunits of the
oxidative phosphorylation complexes (Arnaudo et al. 1992), and splice
variants of a mitochondrial inner-membrane phosphate carrier have been
described in bovine tissues (Dolce et al. 1996).
(4) In humans and other organisms, different processing of mitochon-
drial RNA and protein, leading to tissue specific defects or functions, have
been described. For example, in
Drosophila melanogaster
, the mitochon-
drial large ribosomal RNA can, in germ cell precursor cells, also be
processed for export into the cytoplasm, where it induces pole cell forma-
tion in embryos, a key event in the determination of the germ line
(Kobayashi et al. 1993). A human example is a case of a 22-year-old patient
who died from respiratory failure due to a mitochondrial myopathy. Analy-
sis of tissues from the patient showed that the causative mutation in the
mitochondrial
tRNALeu(UUR)
gene resulted in a RNA processing defect
in skeletal muscle, but not in fibroblasts (Bindoff et al. 1993). Also, in
humans it has been shown that a normally occurring RNA processing inter-
mediate of the heavy-strand polycistronic RNA is more prevalent in lym-
phocytes and liver than in other tissues (Nardelli et al. 1994).
