We report here on the clinical, genetic, and molecular characterization of three Han Chinese pedigrees with
aminoglycoside-induced and
nonsyndromic hearing loss. Clinical evaluation revealed the variable phenotype of
hearing loss including severity, age-at-onset, audiometric configuration in these subjects. Penetrances of
hearing loss in BJ107, BJ108, and BJ109 pedigrees are 35%, 63%, and 67%, respectively. Mutational analysis of the complete mitochondrial genomes in these pedigrees showed the identical homoplasmic A1555G mutation and distinct sets of
mitochondrial DNA (
mtDNA) variants belonging to haplogroups N, F, and M, respectively. Of these variants, the A14693G mutation in the
tRNA(Glu), the T15908C mutation in the
tRNA(Thr), and the T10454C mutation in the
tRNA(Arg) are of special interest as these mutations occur at positions which are highly evolutionarily conserved
nucleotides of corresponding tRNAs. These homoplasmic
mtDNA mutations were absent among 156 unrelated Chinese controls. The A14693G and T10454C mutations occur at the highly conserved bases of the TpsiC-loop of
tRNA(Glu) and
tRNA(Arg), respectively. Furthermore, the T15908C mutation in the
tRNA(Thr) disrupts a highly conserved A-U base-pairing at the D-stem of this
tRNA. The alteration of structure of these tRNAs by these
mtDNA mutations may lead to a failure in
tRNA metabolism, thereby causing impairment of mitochondrial translation. Thus,
mitochondrial dysfunctions, caused by the A1555G mutation, would be worsened by these
mtDNA mutations. Therefore, these
mtDNA mutations may have a potential modifier role in increasing the penetrance and expressivity of the
deafness-associated
12S rRNA A1555G mutation in those Chinese pedigrees.