VARIANTS IN MITOCHONDRIAL tRNA GENE MAY NOT
BE ASSOCIATED WITH THYROID CARCINOMA Lv F1,a, Qian G2,a, You W1,a, Lin H3, Wang XF3, Qiu GS2,
Jiang YS2, Pang LX3, Kang YM4, Jia BF4, Xu JZ5,*, Yu Y1,* *Corresponding Author: Dr. Jinzhong Xu, Department of Clinical Pharmacy, the Affiliated Wenling Hospital
of Wenzhou Medial University, Taiping Nan Road 190, Wenling 317500, People’s Republic of China. Tel./Fax:
+86-(0)576-8620-6288. E-mail: xujzwl@163.com and Dr. Yang Yu, Department of Breast Surgery, Henan Provincial
People’s Hospital, Weiwu Road 7, Zhengzhou 450003, People’s Republic of China. Tel./Fax: +86-(0)371-
6558-0014. E-mail: 510790135@qq.com page: 59
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DISCUSSION
Mutations of mtDNA, as well as nuclear genome,
are associated with various human diseases
and may play important roles in age-related disorders,
including cancer and aging [16]. Alterations
in OXPHOS in tumor cells were originally believed
to play a causative role in malignant growth and tumorigenesis
[17]. On the other hand, mutations in
the mt-tRNA genes have impact on the secondary
and tertiary tRNA structure, and may consequently
cause transcriptional and translational defects and mitochondrial
respiratory chain dysfunction. More than
half of mitochondrial mutations have been located in
mt-tRNA genes which are hot-spots for mitochondrial
pathogenesis [18]. However, we noticed that a certain
amount of mt-tRNA mutations were wrongly classified
as a “pathogenic” mutation, such as the C628T
variant in deafness expression [9].
In this study, we evaluated seven reported mttRNA
variants with thyroid cancer by employing phylogenetic
conservation analysis (Table 1 and Figure 1).
Of these variants, four (G7521A, T10411C, T10463C
and T5655C) were located at the acceptor arm, one
variant (A12308G) localized at the variable loop, one
variant (G4292C) was in the anticodon loop, while
the C4312T variant was at the T arm. By systematic
review and literature searching, we found that only the
A12308G and T5655C variants had been reported to
be associated with mitochondrial diseases, while other
variants were rare polymorphisms and had not been reported
before. Of these, the common variant, A12308G,
had been described with a wide range of clinical disorders
such as stroke [19], and this variant may increase
the risk of developing pigmentary retinal degeneration,
short stature, dysphasia-dysarthria and cardiac conduction
defects [20]. In addition, the T5655C variant had
been reported to increase the penetrance and expressivity
of non syndromic deafness associated with the
tRNASer(UCN) T7511C mutation [21]. However, as the
T5655C variant caused a slight change of ⊿G between
the wild-type and the mutant tRNAAla, it indicated that
it may have been served as a polymorphism.
In order to examine structure-function relationships,
we used the RNA Fold Web Server (http://
rna.tbi.univie. ac.at/cgi-bin/RNAfold.cgi) program
to predict the optimal secondary structures for the
mt-tRNAs through free energy minimization [22,23],
in which the size of the minimum free energy change
indicated the “driving force” behind the reaction, and
the more negative the ⊿G is, the more likely was
the process. We found that a wide spectrum of differences
in the ⊿G of the mt-tRNAs. The largest negative
differences in ⊿G (wild-type)‒⊿G(mutant)<‒3
were found in all these variants, suggesting that the
polymorphic variant was energetically less favorable
than the wild-type form.
Previous studies showed a positive association
between the known tRNALeu(CUN) A12308G variant
and clinical phenotypes. However, Deschauer et al.
[24] considered that this mutation may not increase
the risk of stroke in patients with the tRNALeu(UUR)
A3243G mutation. To address this problem, we performed
a mutational analysis for the A12308G in
thyroid cancer individuals and healthy controls. To
our surprise, there were five patients with this variant,
as well as three control subjects. This finding was
consistent with a recent study by Mohammed et al.
[25], and our data suggested that the A12308G variant
was most probably a neutral polymorphism as it was
a common event in the human genetic population.
Analysis of the CIs of these variants showed that
three of them exhibited high levels of conservation,
including the A12308G, T10463C and T5655C (CI
>70.0%). However, we noticed that not all the pathogenic
mutations were conserved between different
species, such as the Leber’s Hereditary Optic Neuropathy
(LHON) associated ND4 G11778A mutation
[26]. Most importantly, using the cybrid cells carrying
these variants, by examining the steady-state level,
aminoacylation ability were the “gold standards” to
detect the polymorphisms and mutations [27]. Therefore,
based on this study, we found that mt-tRNA
variants may not be involved in the pathogenesis of
thyroid carcinoma.
Declaration of Interest. This study was partly
supported by Zhejiang Provincial Natural Science
Foundation (LQ13H280002, LY12H15001 and
LY12H03001), Henan Basic and Frontier Technology
Research Projects (142300410388 and
132300410048), Wenling Foundation of Science
and Technology (2011WLCB0109, 2014C311051
and 2015C312055), Project of Medical Technology
of Zhejiang Province (2013KYA130, 2015KYB234,
2015KYA 154, 2016KYA166 and 2016KYB275),
Public Project of Science and Technology of Wenzhou
City (Y20140739 and Y20150094), Ningbo Natural
Science Foundation (2015A610234), and Xiangshan
Science and Technology Project (2015C6005). The
authors report no conflicts of interest. The authors
alone are responsible for the content and writing of
this article.
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