Biology Reference
In-Depth Information
mitochondrial DNA defect may be responsible. Additional evidence for a
genetic basis for aminoglycoside susceptibility comes from animal studies.
Macaque monkeys are resistant to dihydrostreptomycin, while the patas
monkeys are highly sensitive to that drug (Stebbins et al. 1981).
Analysis of three Chinese families, in which several individuals developed
deafness after the use of aminoglycosides, identified the A1555G mutation
in the
12S
ribosomal RNA gene in all three of them, but not in hundreds
of controls (Prezant et al. 1993). In addition, a small proportion of “spo-
radic” Chinese patients, without a positive family history for aminoglyco-
side ototoxicity, exhibit this particular mutation (Fischel-Ghodsian et al.
1993). These findings were confirmed in two Japanese families and addi-
tional Chinese sporadic cases (Hutchin et al. 1993). Subsequently, the same
mutation was found in families and sporadic patients with aminoglycoside
ototoxicity from Zaire, the United States, Mongolia, Spain, South Africa,
and Israel (Matthijs et al. 1996; Fischel-Ghodsian et al. 1997; Pandya et al.
1997; El-Shahawi et al. 1997; Estivill et al. 1998; Gardner et al. 1997; Shohat
et al. 1999). Interestingly, in one streptomycin-induced deaf individual with
a strong familial history of aminoglycoside-induced hearing loss and the
A1555G mutation, detailed vestibular examination revealed severe hearing
loss, but completely normal vestibular function (Braverman et al. 1996).
Because the A1555G mutation in the mitochondrial
12S
rRNA gene
accounts only for a minority of patients with aminoglycoside ototoxicity, it
is possible that other susceptibility mutations may be found in the same
gene. Mitochondrial DNA from 35 Chinese sporadic patients with amino-
glycoside ototoxicity and without the A1555G mutation was analyzed for
sequence variations in the
12S
rRNA gene. Three sequence changes were
found, but only one of them, an absence of a thymidine at position 961 with
varying numbers of cytosines inserted (DT961Cn), appeared likely to be a
pathogenic mutation (Bacino et al. 1995). Analysis of 34 similar patients in
the United States, of varying ethnic backgrounds, did not reveal this muta-
tion, but recently an Italian family was reported in which five maternally
related members became deaf after aminoglycoside treatment; they were
all found to have the DT961Cn mutation (Casano et al.1999). This sequence
change was not found in 799 control individuals (Bacino et al. 1995).
3.4 Mitochondrial DNA Mutations and Presbycusis
Another condition associated with acquired heteroplasmic mutations and
hearing loss is presbycusis. Presbycusis is the hearing loss that occurs with
age in a significant proportion of individuals. Because mtDNA mutations,
and the resulting loss of oxidative phosphorylation activity, seem to play an
important role in the aging process (reviewed by Nagley et al. 1993), it
seems likely that mtDNA mutations in the auditory system might lead to
presbycusis. Recently, the spiral ganglion and membranous labyrinth from
archival temporal bones of five patients with presbycusis were examined
for mutations within the mitochondrially encoded cytochrome oxidase II
