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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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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