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 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
page: 6

DISCUSSION

In this study, we have performed clinical, genetic and molecular characterization of a three-generation Han Chinese family with AINHL. Hearing impairment as a sole clinical phenotype was mostly present in the maternal lineage of this pedigree, suggesting that the mtDNA variant was the molecular basis for this disorder. As shown in Figure 1, this family exhibited a high penetrance of hearing loss, in particular, the penetrance of hearing loss in this family was 80.0 and 40.0%, when aminoglycoside was included and excluded. Sequence analysis of the mitochondrial genome showed the presence of C1494T pathogenic variant in the 12S rRNA gene, in fact, this pathogenic variant was first identified in a large Chinese family with AINHL [6]. Functional characterizations of cell lines derived from the C1494T pathogenic variant led to only mild mitochondrial dysfunction and sensitivity to aminoglycosides [11]. In addition, three affected matrilineal relatives exhibited the various severities, age at onset of hearing loss, suggesting that the C1494T pathogenic variant itself was insufficient to produce the clinical phenotypes; other modifying factors such as environmental factors, aminoglycosides, mitochondrial haplotype and nuclear genes were involved in deafness expression. In addition, the mitochondrial haplotype has been shown to influence the penetrance of hearing loss associated with mtDNA primary mutations. In particular, mtDNA variants at positions 4216 and 13708, acting as second Lebers’ hereditary optic neuropathy (LHON) variants, were implicated to increase the penetrance of the deafnessassociated A7445G pathogenic variant [19]. Moreover, the T5628C variant in tRNAAla was thought to have a modifying role in the phenotypic manifestation of the C1494T pathogenic variant in a Han Chinese family [20]. In this study, the sequence analysis of the entire mitochondrial genome identified a set of polymorphisms, apart from C1494T and G7444A pathogenic variants, other variants in the mitochondrial genome showed no evolutionary conservation. As shown in Figures 3 and 4, the G7444A pathogenic variant resulted in a read-through of the stop condon AGA of the COI message, thereby adding three amino acids (Lys-Gln-Lys) to the C-terminal of the polypeptide. Thus, the mutated polypeptide may retain a partial function. Alternatively, the G7444A pathogenic variant was adjacent to the site of 3’ end endonucleolytic processing of the L-strand RNA precursor, spanning tRNASer(UCN) and ND6 mRNA [19]. The previous study showed that the A7445G pathogenic variant in the precursor of tRNA Ser(UCN) led to a failure in the processing of the L-strand RNA precursor, thereby causing a marked decrease of the steady-state levels of tRNASer(UCN) and ND6 mRNA [19]. Thus, the G7444A pathogenic variant, similar to the A7445G pathogenic variant, may also cause a defect in the processing of the L-strand RNA precursor, thus causing mitochondrial dysfunction. Although aminoglycoside was the predominant factor for hearing impairment, the G7444A pathogenic variant may also play an important role in the phenotypic expression of the C1494T pathogenic variant in this Chinese family. Moreover, due to the lack of any functional variants in GJB2 and TRMU genes, those nuclear genes may not play active roles in deafness expression. Taken together, our data showed that the combination of the C1494T and G7444A pathogenic variants in the mitochondrial genome, as well as the aminoglycosides may account for the high penetrance and expression of hearing loss in this family. In summary, our study indicated that the combination of the C1494T and G7444A pathogenic variants in the mitochondrial genome, combined with the aminoglycosides, may account for the high penetrance and expression of AINHL in this family. Moreover, the incomplete penetrance, variable degree of hearing loss in matrilineal relatives suggested that other modified factors, such as epigenetic modification and environmental factors may contribute to the clinical expression of hearing loss in this family.



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