Balkan Journal of Medical Genetics

THE MITOCHONDRIAL tRNAGly T10003C MUTATION MAY NOT BE ASSOCIATED WITH DIABETES MELLITUS
Yuan Q, Zhao ZG, Yuan HJ
*Corresponding Author: Dr. Qian Yuan, Department of Endocrinology and Metabolism, People’s Hospital of Zhengzhou University, Weiwu Road 7, Zhengzhou, Henan Province, People’s Republic of China. Tel/Fax: +86-0371-6558-0014. E-mail: yuanqian001@126.com
page: 53

DISCUSSION

In this study, we investigated the potential pathogenic role of T2DM associated tRNAGly T10003C mutation. Mitochondria are the powerful machine in cells whose primary role is to generate adenosine triphosphate (ATP), through OXPHOS. More recently, the role of the mitochondrial dysfunction in the pathogenesis of DM has been studied extensively. Alterations in mitochondrial function in human β cells resulted in the impaired glucose- stimulated insulin secretion. Mutations in mtDNA, especially mt-tRNA genes, found to be associated with DM. In particular, one of the most common pathogenic mtDNA mutation was A3243G in the tRNALeu(UUR) gene. This mutation was reported to decrease the steady-state level of the tRNALeu(UUR) and resulted with the impairment of amino-acylation ability [17], and subsequently, mitochondrial protein synthesis failed [18]. However, there is a number of mt-tRNA variations that were wrongly classified as a “pathogenic” mutation, such as the C628T variant [9,19]. With this regard, this study reassessed the possible association between the T10003C mutation and DM. Database searches for the presence of this mutation led us to identify two potential records that were mentioned in the results sections [15,16]. Mutational analysis of the proband from the maternally inherited DM identified a set of polymorphisms; some of these were obviously pathogenic in the human population, for example, the G15924A mutation in the tRNAThr gene, was reported to be a fatal infantile respiratory enzyme deficiency- associated pathogenic mutation [20]. Moreover, the 12S rRNA T1095C mutation was a deafness associated primary mutation [21], whereas the A6 A8701G mutation was found to be associated with cardiomyopathy in the Han Chinese population [22]. Therefore, it seemed that beside the T10003C mutation, other mutations may also contribute to DM in this Chinese family. At the molecular level, the T10003C mutation localized at the D-stem of the tRNAGly gene (position 13), was not very conserved among different species (Figure 1). Furthermore, to explore the structure to function relations, we used the RNA Fold Webserver program to predict the optimal secondary structure of tRNAGly through free energy minimization. As shown in Figure 2, it was quite obvious that T10003C mutation failed to cause the alternation of tRNAGly structure, moreover, we did not detect the T10003C mutation in 500 unrelated DM patients and 300 control subjects, suggesting that it may be a genetic polymorphism rather than a pathogenic mutation. In conclusion, there was no direct evidence to support the association between the T10003C mutation and DM. Further studies including larger samples and functional analyses are needed to verify this conclusion. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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