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Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency

  • Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Primary ovarian insufficiency (POI) is a heterogeneous, multifactorial disorder. Though genetic anomalies, infections, autoimmune disorder and hormonal imbalance are few of the causes of POI, in the majority of patients (50–60%) no etiology has been identified. Mitochondrial bioenergetics and biogenesis play an important role in oocyte and embryo development, whereas mtDNA integrity and content are essential for the normal development of oocytes. ATPase6 helps to maintain the mt genome integrity, and mutations in ATPase6 are associated with overproduction of reactive oxygen species (ROS) in a variety of diseases; however, its role in POI has not been evaluated. Therefore, we planned to evaluate the potential role of ATPase6 gene mutations and associated oxidative stress in idiopathic cases of POI.

Methods

This pilot study included: 20 cases of POI with FSH level of >40 mIU/ml; 4 cases of occult ovarian insufficiency (occult OI) with irregular menses and mean FSH levels of 16.4 mIU/ml; and 20 age-matched healthy female controls (FSH 2–5 mIU/ml). ROS levels in blood plasma were measured by luminol-dependent chemiluminescence assay and the ROS values were expressed as relative light unit per minute (RLU/min). mtDNA ATPase6 gene was amplified and sequenced from the blood lymphocyte DNA.

Results

Of all, 50% patients showed nucleotide changes in the ATPase6 gene, as compared to 10% in controls, and the majority of these mutations were non-synonymous. ATPase6 mt.8684 C>T and mt.9094 C>T were found to be significantly (P < 0.005) higher in cases as compared to controls. ROS levels were found to be significantly (P < 0.005) higher in POI and occult OI patients compared to controls and nucleotide changes were found to positively correlate with ROS levels. Moreover, ROS production was found to positively correlate (r = 0.7038, P < 0.001) with FSH levels of the patients (POI and OI) compared to controls.

Conclusions

This pilot study clearly demonstrates for the first time ATPase6 gene nucleotide alterations and elevated ROS levels in idiopathic cases of POI. Therefore, it may be possible that OS associated with ATPase6 gene mutation may be causal in idiopathic cases of premature OI. However, larger studies with inclusion of more cases of both POI and occult OI are required to strongly establish the correlation between oxidative stress and mitochondrial nucleotide alterations in the pathogenesis of POI. Such cases with OS-induced POI may benefit immensely by early diagnosis and prompt antioxidant administration.

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Conflict of interest statement

We declare that we have no conflict of interest.

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Authors and Affiliations

  1. Laboratory for Molecular Reproduction and Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India

    S. Venkatesh, M. Kumar, A. Sharma & Rima Dada

  2. Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences, New Delhi, India

    A. Kriplani

  3. Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India

    A. C. Ammini

  4. ART Centre, Army Research and Referral Hospital, New Delhi, India

    P. Talwar

  5. Center for Reproductive Medicine, Glickman Urological and Kidney Institute, Obstetrics and Gynecology and Women’s Health Institute, Cleveland Clinic, Cleveland, OH, USA

    A. Agarwal

  6. Department of Anatomy, All India Institute of Medical Science (AIIMS), New Delhi, 110029, India

    Rima Dada

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  1. S. Venkatesh
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  2. M. Kumar
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  3. A. Sharma
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  4. A. Kriplani
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  5. A. C. Ammini
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  6. P. Talwar
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  7. A. Agarwal
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  8. Rima Dada
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Correspondence to Rima Dada.

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Venkatesh, S., Kumar, M., Sharma, A. et al. Oxidative stress and ATPase6 mutation is associated with primary ovarian insufficiency. Arch Gynecol Obstet 282, 313–318 (2010). https://doi.org/10.1007/s00404-010-1444-y

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  • DOI: https://doi.org/10.1007/s00404-010-1444-y

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