Genetic Epidemiology of Deafness - Genetics of Auditory Disorders - page 79

there are three other mitochondrial mutations in which deafness plays a
much more prominent role. One form of maturity onset diabetes of youth
(MODY) has been identified which is caused by an A8334G substitution in
the mitochondrial tRNA Leu gene (van den Ouweland et al. 1992). Most
of these patients also develop a late-onset hearing loss, which can be quite
rapid in its progression. Matrilineal transmission is a characteristic feature
of these families. The A1555G substitution in the mitochondrial 12S rRNA
gene is now known to be the underlying cause for many cases of amino-
glycoside ototoxicity (Fischel-Ghodsian et al. 1995). Aminoglycosides nor-
mally bind to bacterial rRNA molecules and exert their therapeutic effect
by interfering with normal protein synthesis. The A1555G mutation makes
the human mitochondrial ribosome more “bacteria-like” by creating a
binding site for streptomycin, where it also interfaces with the fidelity of
protein synthesis. The A1555G mutation has been shown to have a high
prevalence in deaf populations in Mongolia, China, Japan, and Spain, and
also appears to be the cause of hearing loss in some patients with no history
of exposure to streptomycin. Whether there are natural compounds, or
other toxins that can mimic aminoglycosides is not clear, nor is it clear why
the effects of the gene are strictly limited to the ear, but at the same time
expression can be so variable. Nuclear or mitochondrial modifier genes
have been proposed as one possible explanation for the observed variabil-
ity. Finally, an A7445G substitution immediately adjacent to the tRNA TRY
has been identified in several families with matrilineal hearing loss, in some
of which ichthyosis was also found (Reid et al. 1994). The A7445G muta-
tion interferes with the normal processing of the polycistronic message
coded by the mitochondrial light chain. In a sample of 380 deaf students
from Mongolia, loss of the Xba 1 restriction site was found in nine students,
but sequencing revealed substitutions involving the 7444 and 7443 residues
in addition to nt7445. Because these adjacent mutations all result in deaf-
ness, they may well define the binding site for the elusive endonuclease that
initiates the processing of the light-strand message. Twelve of the students
carried the A1555G substitution including, six who also had the 7444
change. Available clinical and audiologic data suggested that the individ-
uals with the double mutations were more severely affected, raising the
possibility of an epistatic interaction in subjects with the double mutant
(Pandya et al. 1999).
4.4 Structure
Several genes for deafness code for structural proteins that appear to be
required for normal hearing. The X-linked gene Col4A codes for a form of
collagen that is deficient in Alport's syndrome. In the kidney, this protein
is an essential constituent of the basal membrane of the glomerulus. In its
absence, the membrane becomes porous, allowing proteins and red cells to
enter the glomerular filtrate. Although the physiologic role of the protein