THE MITOCHONDRIAL COI/tRNASER(UCN) G7444A MUTATION MAY BE ASSOCIATED WITH HEARING IMPAIRMENT IN A HAN CHINESE FAMILY
Ding Y, Xia B-H, Teng Y-S, Zhuo G-C, Leng J-H,
*Corresponding Author: Dr. Jian-Hang Leng, Central Laboratory, Hangzhou First Peopleís Hospital, Nanjing Medical University, Huansha Road 261, Hangzhou, Peopleís Republic of China. Tel./Fax: +86-0571-87065701. E-mail: lengjh5@163.com
page: 6

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 Peopleís 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 probandís 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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