Biology Reference
In-Depth Information
A third mtDNA mutation, a cytosine insertion at position 7472
(Cins7472) in the
tRNAser(UCN)
gene, was identified in one large Dutch
family, with 27 deaf individuals (Verhoeven et al. 1999). The same mutation
had been previously described in a Sicilian family with 13 members with
hearing loss, seven of whom had other neurological symptoms, such as
ataxia and myoclonus (Tiranti et al. 1995). In the Dutch family, only a
single individual had neurological symptoms, and the hearing loss was
sensorineural-progressive with onset in early adulthood. Most of the indi-
viduals over 30 years of age were deaf, indicating that the penetrance in
this family is high. The mutation is heteroplasmic, although most individu-
als had over 90% of abnormal mitochondrial chromosomes in the tissue
examined.
Recently, a large African-American pedigree with maternal inheritance
of nonsyndromic hearing loss has been identified. The A1555G, A7445G,
and Cins7472 mutations, as well as large deletions/rearrangements in the
mtDNA were excluded, suggesting the existence of a fourth mitochondrial
mutation associated with nonsyndromic hearing impairment (Friedman
et al. 1999). This was confirmed with the identification of a close-to-
homoplasmic mutation, T7511C, in the
tRNAser(UCN)
gene (Sue et al.
1999).
3.3 Mitochondrial DNA Mutations and Ototoxic
Hearing Loss
Aminoglycoside ototoxicity is one of the most common causes of acquired
deafness. Although vestibulocochlear damage is nearly universal when high
drug levels are present for prolonged periods, at lower drug levels there
appears to be a significant genetic component influencing susceptibility to
aminoglycoside ototoxicity. The existence of families with multiple individ-
uals with ototoxic deafness induced by aminoglycoside exposure was
noticed early on. The first families with more than two members with
streptomycin-induced hearing loss were described in the Japanese litera-
ture in 1957 (for review, see Higashi 1989). Prazic et al. (1964) described a
family with four sisters who developed hearing loss after streptomycin
injections. Tsuiki and Murai (1971) described 16 families in which two or
more members had aminoglycoside ototoxicity. Konigsmark and Gorlin
(1976) summarized most existing descriptions of familial aminoglycoside
ototoxicity and concluded that inheritance of the predisposition is proba-
bly autosomal dominant with incomplete penetrance. However, they also
noted that no male-to-male transmission has been seen, and suggested that
the inheritance pattern might be multifactorial. Higashi (1989) reviewed the
literature, and concluded that the most likely explanation for the maternal
inheritance observed is a mitochondrial DNA defect. Hu et al. (1991)
described another 36 families in China with maternally transmitted
predisposition to aminoglycoside ototoxicity, and concluded also that a
