THE MITOCHONDRIAL COI/tRNASER(UCN) G7444A MUTATION
MAY BE ASSOCIATED WITH HEARING IMPAIRMENT
IN A HAN CHINESE FAMILY Ding Y1,2, Xia B-H3, Teng Y-S2,4, Zhuo G-C1,2, Leng J-H1,2,* *Corresponding Author: Dr. Jian-Hang Leng, Central Laboratory, Hangzhou First People’s Hospital, Nanjing Medical University,
Huansha Road 261, Hangzhou, People’s Republic of China. Tel./Fax: +86-0571-87065701. E-mail: lengjh5@163.com
Y. Ding and B-H. Xia contributed equally for this study. page: 43
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RESULTS
Clinical Features of the Han Chinese Family with
AINHL. All patients from the Han Chinese family lived in
Hangzhou City of Zhejiang Province. The proband (III-2)
was an infant born in Hangzhou First People’s Hospital.
As shown in Table 1 and Figure 2, the proband exhibited
bilateral hearing impairment (90 dB right ear and 95 dB
left ear). A comprehensive history and physical examination
were performed to identify any syndromic findings,
and the history of use of aminoglycosides. Moreover, we
noticed that the proband’s mother (II-5), a young woman
at the age of 26 years; had been administered gentamicin
(5 mg/kg/dose, 10 days) for fever when she was 18-yearsold.
She developed the profound hearing loss 2 months
after the drug administration. It is interesting to note that
two matrilineal relatives (I-2, II-5), who had a history
of exposure to gentamicin and streptomycin, exhibited a
severe hearing impairment in this maternal kindred, suggesting
that the aminoglycosides may play an important
role in this disorder.
Screening for the Mutations in the Mitochondrial
Genome. The maternal transmission of hearing loss in
this family suggested a mitochondrial involvement and
led us to analyze the mitochondrial genome of matrilineal
relatives (I-2, II-5, III-2) and the healthy subjects. We first examined the known mtDNA pathogenic variants
associated with deafness by PCR amplification (A1555G,
C1494T, A7445G, T7510C and T7511C). As shown in Figure
3, the PCR-Sanger sequencing identified two known
pathogenic variants: the C1494T in the 12S rRNA gene
and the G7444A in the COI/tRNASer(UCN) gene. However,
we did not detect the presence of the A1555G pathogenic
variant in the 12S rRNA gene or the A7445G, T7510C,
T7511C pathogenic variants in the tRNASer(UCN) gene in
these matrilineal relatives.
To elucidate the molecular basis for maternally transmitted
deafness, 24-overlapping DNA fragments spanning
the entire mitochondrial genome were PCR-amplified and
sequenced. The comparison of the resultant sequence with
the Cambridge consensus sequence identified a set of polymorphisms,
as shown in Table 2. Among these, there were
five variants in the D-loop, two known variants in the 12S
rRNA and two variants in the 16S rRNA genes, while other
variants were mainly localized at protein-coding genes.
Moreover, we noticed that there were four amino acid
substitutions caused by corresponding mtDNA variants occurring
in different polypeptides. These missense variants
included the ND1 C3497T (A64V), A6 A8860G (T112A),
ND3 A10398G (T114A) and Cytb A15326G (T194A).
These variants in rRNAs and polypeptides were further
evaluated by phylogenetic analysis from other organisms
including mouse [16], bovine [17] and Xenopus laevis
[18]. However, none of the variants in the polypeptides
were highly evolutionarily conserved and implicated to
have functional consequences.
Mutational Analysis of the GJB2 and TRMU
Genes. To examine the role of the GJB2 and TRMU genes
in phe-notypic expression of the C1494T pathogenic variant,
we performed the mutational screening of GJB2 and
TRMU exon 1 in matrilineal relatives who carried the
C1494T pathogenic variant. However, none of the variants
were found in the GJB2 and TRMU genes, suggesting that
the GJB2 and TRMU genes may not play an important role
in this Chinese family.
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