Research paperMitochondrial tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations may be associated with PCOS and metabolic syndrome
Introduction
Polycystic ovary syndrome (PCOS) is a serious health problem, according to a recent report, approximately 5%–10% reproductive women suffered from this disorder (Goodarzi et al., 2011). PCOS can be caused by an imbalance of sex hormones, characterized by chronic anovulation, hyperandrogenism, hyperinsulinemia and infertility (Jiao et al., 2014). In addition, patients with this disease are at a risk of type 2 diabetes mellitus (T2DM), cardiovascular events, as well as metabolic syndrome (MetS) (Rajendran et al., 2009, Christakou and Diamanti, 2008). Moreover, in accordance with the national health statistic reports, the percentage of MetS in America was almost 34% in the general population with the age of 20 years old (Ervin, 2009). In particular, it has been estimated that 60–80% DM patients manifestated MetS.
Even today, the molecular mechanism underlying MetS remains poorly understood, but it is believed that the etiology of MetS may be related to the alternations in genetic factors. Mutations in nuclear encoded genes, such as VEGF and PPARD, are considered as susceptibility genes of MetS (Ghazizadeh et al., 2017, Tang et al., 2016). However, the association between variants in mitochondrial genome and MetS is less characterized.
Mitochondrial DNA (mtDNA) is a 16,569 bp molecule that encodes 22 tRNAs, 2 rRNAs, as well as 13 polypeptides which are essential for generation energy in the form of ATP via oxidative phosphorylation (OXPHOS) (Picard et al., 2016). Furthermore, since mtDNA lacks histones protection and does not have a DNA repair system, its mutation rate is much higher than nuclear DNA (Selim and Hassaan, 2017).
Previously, with the purpose of understanding the association between mtDNA mutations and PCOS, we sequenced the complete mitochondrial genomes from 160 PCOS patients and 80 with age- and body mass index (BMI)-matched healthy subjects from Hangzhou First People's Hospital. We found that mutations in mt-tRNA genes may be involved in the development of PCOS. For example, the tRNAGln T4395C, tRNACys G5821A, tRNAAsp A7543G, tRNAArg T10454C, tRNAGlu A14693G, tRNASer(UCN) C7492T and tRNALeu(UUR) A3302G mutations which occurred at the highly evolutionary conserved positions of mt-tRNA, may result in the structural and functional alternations and consequently lead to the failure in mt-tRNAs metabolism (Zhuo et al., 2012, Ding et al., 2016b, Ding et al., 2016c, Ding et al., 2017). In particular, the A3302G mutation on the acceptor arm of tRNALeu(UUR) caused the mitochondrial dysfunction via the reduction of mitochondrial copy number (Ding et al., 2016b). To explore the contribution of mtDNA to PCOS, we enrolled more patients from our Hospital and screened the potential pathogenic mtDNA mutations by PCR-Sanger sequencing. In the present study, we reported a Chinese pedigree with MetS, combined with PCOS. Analysis of the mitochondrial sequence led us to identify the co-existence three tRNA mutations: tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G. To further understand the contributions of these mutations to the clinical phenotypes, we measured the MMP, ATP and ROS levels in PMNs from the individuals carrying these mt-tRNA mutations, moreover, the mtDNA copy number was determined using real-time quantitative PCR.
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Subjects
A maternally inherited Chinese pedigree, which manifestated both MetS and PCOS, was ascertained in Hangzhou First People's Hospital (Fig. 1). In addition, 300 age- and gender-matched healthy subjects were enrolled in this investigation. Informed consent was protocol approval by the Ethics Committee of Hangzhou First People's Hospital, affiliated to Nanjing Medical University. Moreover, the written informed consent was obtained from each individual who participated in this study.
Diagnosis of MetS and PCOS
The definition
Clinical and biochemical characteristics
We collected a Chinese family with MetS and PCOS from Hangzhou First People's Hospital, as displayed in Fig. 1. There were seven matrilineal relatives in this pedigree, while three of them affected different phenotypes of endocrine disorders, the sex ratio between male and female was 1:1, with the age ranged from 31 to 66 years old. The proband, aged 31 came to the Department of Gynecological and Obstetrics of Hangzhou First People's Hospital because of her abnormal menstruation. According to
Discussion
The current study reported the molecular and biochemical features of a Chinese pedigree with MetS, combined with PCOS. Many of the anthropometric and metabolic abnormalities of PCOS overlapped with components of the MetS, a clustering of both lipid and non-lipid risk factors that identified individuals at increased risk for coronary heart disease and T2DM (Osei and Gaillard, 2017). However, maternally inherited MetS, especially co-existence with PCOS, was infrequent in general population.
Conclusions
In conclusion, the present study demonstrated the association between mt-tRNA mutations and MetS, combined with PCOS in a Han Chinese family. The tRNALeu(UUR) C3275T, tRNAGln T4363C and tRNALys A8343G mutations should be regarded as risk factors for further molecular diagnosis of MetS and PCOS. Thus, our findings provided novel insight into the molecular mechanism, management of maternally transmitted MetS. The main limitation of the present study was relative small sample size; moreover, the
Conflict of interest
None.
Acknowledgements
This work is supported by the grants from Ministry of Public Health from Zhejiang Province (no. 2013KYA158), Hangzhou Bureau of Science and Technology (no. 20150633B16) and Natural Science Foundation of Zhejiang Province (no. LY14H270008; LY15H280007).
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The first two authors have contributed equally for this work.