Biology Reference
In-Depth Information
Based on these four lines of evidence, it is proposed that cochlea-specific
subunits of mitochondrial ribosomes or RNA processing proteins interact
abnormally with the mitochondrial defect, leading to insufficient oxidative
phosphorylation, or loss of a secondary function in the cochlea. Also, vari-
ation in the coding sequence for some of these proteins may explain the
penetrance differences observed among patients. Mitochondrial RNA pro-
cessing and translation is a complex process, which occurs exclusively in the
matrix of the mitochondria. It requires nuclear-encoded proteins for every
step, and has characteristics reminiscent of the bacterial origin of the mito-
chondrial genome. Estimates of the number of proteins involved range
from 200 to 300, and only a small number of these proteins have been iden-
tified. Additional proteins can be identified by a variety of methods. For
example, the mitochondrial ribosomal
S12
gene was identified by cyber-
cloning (Johnson et al. 1998), and this protein has been used as a bait in the
yeast dihybrid system to identify a second protein that is an excellent
candidate for being another mitochondrial ribosomal protein. All the new
proteins identified through such methods are tested for isoforms and
cochlea-specific splice variants, using cochlea-specific cDNA libraries
(Giersch and Morton, Chapter 3). A more direct approach to the identifi-
cation of some of these proteins is through isolation of mitochondrial
ribosomes from cochlea and another tissue, resolution by 2D gel electro-
phoresis, and microsequencing of proteins with different electrophoretic
characteristics from individual spots. The bovine model system has been
established for this purpose (Matthews et al. 1982; O'Brien and Denslow,
1996), and identity correspondence to the human mitoribosomal system has
been established by 2D PAGE co-electrophoretic separations of human and
bovine mitoribosomal proteins (Matthews et al. 1982).
7. Summary
In conclusion, mitochondria-related hearing loss can be caused by a variety
of mutations, and can present in a variety of clinical forms with different
degrees of severity. These mutations are not uncommon and, owing to the
susceptibility of individuals with the A1555G and DT961Cn mutations and
their maternal relatives to aminoglycosides, are important to diagnose.
Despite the fact that these mostly homoplasmic mitochondrial mutations
represent the simplest model of a mitochondrial DNA disease, it remains
unclear how mtDNA mutations lead to the clinically crucial features of pen-
etrance and tissue specificity. Within the same family, some individuals with
the mutation can have profound hearing loss, while others have completely
normal hearing, and only the hearing is affected although all tissues have
the mutation and are dependent on mitochondrial ATP production. Exper-
imental approaches using spontaneous mouse models of mitochondrial
hearing impairment, or direct investigation of the most likely biochemical
