Biology Reference
In-Depth Information
chemical differences between lymphoblastoid cell lines of hearing and deaf
family members with the identical mitochondrial chromosomes provide
direct support for the role of nuclear factors (Guan et al. 1996). An exten-
sive genome-wide search has led to the conclusion that this nuclear effect
is unlikely to be due to a single nuclear gene (Bykhovskaya et al. 1998).
Thus, the model that emerges for explaining penetrance is a threshold
model, where a combination of environmental, mitochondrial, and nuclear
factors can push a cell over a threshold, with dramatic clinical differences
on either side of this threshold.
The second major biological question relates to tissue specificity: If
a homoplasmic mutation affects oxidative phosphorylation (the only
known function of the human mitochondrial chromosome and an essential
process in every nucleated cell of the human body), it is unclear how the
clinical defect remains confined to the cochlea, rather than affecting every
tissue.
6. Experimental Approaches to Elucidate
the Pathophysiology of Mitochondrial
DNA Deafness Mutations
The experimental approaches to elucidate the pathophysiological pathways
of the mtDNA deafness mutations are limited by the absence of a
spontaneous or induced animal model for any inherited mitochondrial dis-
order. This is mainly due to the lack of experimental ways to manipulate
the mitochondrial chromosome and transfer it into the mitochondrial cyto-
plasm. A collaborative study involving the Jackson Laboratories has been
established to screen all hearing impaired mice for differences in their
mitochondrial genomes. Pending the identification of such a spontaneous
mutant, and given the lack of success with the genetic approach to identify
a nuclear factor influencing the phenotype of the A1555G mutation
(Bykhovskaya et al. 1998), a direct approach is proposed. It is hypothesized
that degree of penetrance and tissue specificity depend on components of
mitochondrial RNA processing and translation, and that cochlea-specific
proteins or splice variants that interact with mutated mitochondrial RNA
can be identified. Four lines of evidence implicate mitochondrial RNA pro-
cessing and translation in the pathophysiological pathway between mtDNA
mutation and hearing loss. Thus, components of these systems may be
responsible for the tissue specificity and penetrance variability observed in
patients:
(1) All the mtDNA mutations associated with nonsyndromic hearing loss
involve ribosomal or transfer RNA, or in the case of the A7445G mutation,
noncoding DNA. That is, none of the known mtDNA mutations associated
with hearing loss causes a structural change in any of the 13 proteins
