Biology Reference
In-Depth Information
plasmic A1555G mutation in the mitochondrial 12S ribosomal RNA gene
was identified as the pathogenic mutation (Prezant et al. 1993).
While subsequently many pedigrees and individual patients have been
described with the same A1555G mutation, in all these cases the hearing
loss occurred only after aminoglycoside exposure (Hutchin et al. 1993;
Fischel-Ghodsian et al. 1993; Matthijs et al. 1996; Fischel-Ghodsian et al.
1997b; Pandya et al. 1997; Gardner et al. 1997). However, recently a signif-
icant number of pedigrees in Spain, with family members who went deaf
with and without aminoglycosides, have been described (El-Schahawi et al.
1997; Estivill et al. 1998). In particular, the study by Estivill et al. (1998) is
remarkable for two reasons, both of which indicate a higher than previously
expected frequency of this mutation. First, 19 families were found to have
the A1555G mutation out of the total of 70 families with sensorineural
hearing loss that were included in the study. Even if the selection criteria
led to a bias towards families with multiple affected individuals, and even
when only the individuals without aminoglycoside exposure are considered,
the frequency of familial sensorineural hearing loss due to the A1555G
mutation is still unexpectedly high. Second, the fact that the mutation was
identified on different haplotypes indicates that it is likely that this muta-
tion exists in other populations as well, and may not be rare. It is also inter-
esting to notice that the age of onset of hearing loss in the Spanish families
was rarely congenital, which is different from the Arab-Israeli pedigree.
Two similar families were identified recently in Italy, with 17 deaf family
members who have the A1555G mutation and no exposure to aminoglyco-
sides (Casano et al. 1998).
Another close to homoplasmic, inherited mutation leading to hearing loss
is the A7445G mutation. It was first described in a family from Scotland,
and confirmed in two unrelated pedigrees from New Zealand and Japan
(Reid et al. 1994a; Fischel-Ghodsian et al. 1995; Sevior et al. 1998). In the
New Zealand and Japanese pedigrees, the skin condition palmoplantar
keratoderma also segregated in the maternal line (Sevior et al. 1998). Inter-
estingly, the penetrance of this mutation for hearing loss in the Scottish
pedigree is quite low, while in the New Zealand and Japanese pedigrees it
is very high. Thus, in similarity to the Arab-Israeli pedigree, the mtDNA
mutation by itself does not appear to be sufficient to cause hearing loss, but
requires additional genetic or environmental factors, which seem to be rare
in the Scottish pedigree and common in the New Zealand and Japanese
pedigrees. The difference in penetrance in this situation appears to be due
to a difference in mitochondrial haplotype. In the New Zealand pedigree,
complete sequencing of the mtDNA revealed three additional sequence
changes in complex I protein genes, two of which have been also labeled as
secondary Leber's hereditary optic neuroretinopathy mutations (Fischel-
Ghodsian et al. 1995). Since these or similar sequence changes are not
present in the Scottish pedigree (Reid et al. 1994b), the mitochondrial
haplotype appears to account for the differences in penetrance.
