BRCA2 deficiency is a potential driver for human primary ovarian insufficiency

Yilong Miao,Zhaokang Cui,Bo Xiong,Pan Wang,Mo Li,Yong Fan,Mo Yang,Bingteng Xie,Sen Li

doi:10.1038/s41419-019-1720-0

Abstract

Reproductive problem has been one of the top issues for women health worldwide in recent decades. As a typical female disease, primary ovarian insufficiency (POI) results in a loss of ovarian follicles and oocytes that thus destroys women fertility. However, due to the complex of POI etiology and rare resource of human POI oocytes, few biomarkers have been identified in clinics and no effective strategy could be applied to treat POI patients. In the search of possible association between DNA damage and POI by Smart-Seq2 and RT2 profiler PCR array, we find that BRCA2, a core DNA repair gene for homologous recombination shows significantly lower expression in two POI patient oocytes. In line with this, we generated oocyte-specific knockout mouse model driven by Gdf9-Cre. The Brca2-deficient mice are infertile because of the arrested follicle development and defective oocyte quality caused by the accumulation of DNA damage. Notably, ectopic expression of Brca2 in Brca2-deficient oocytes could partially restore the oocyte maturation and chromosome stability. Collectively, our data assign a definite deficiency to BRCA2 as a POI driver during follicle development and oocyte maturation, and provide a potential fertility treatment strategy for POI patients induced by BRCA2 deficiency.

Highlights

Primary ovarian insufficiency (POI), known as premature ovarian failure or premature menopause, is defined as a loss of ovarian function before the age of 40 and diagnosed by elevated serum follicle-stimulating hormone (FSH) levels (>40 IU/L), which accounts for one major cause of female infertility[1,2]
Downregulation of BRCA2 in human POI oocytes To investigate potential involvement of DNA damage response (DDR) network in POI etiology, we began the experiment with clinical samples of oocytes from POI patients
We Discussion BRCA genes belong to the family of ataxia-telangiectasia mutated (ATM)-mediated DNA double-strand breaks (DSBs) repair signaling pathway that plays a critical role in the safeguarding of DNA integrity[23]

Summary

Introduction

Primary ovarian insufficiency (POI), known as premature ovarian failure or premature menopause, is defined as a loss of ovarian function before the age of 40 and diagnosed by elevated serum follicle-stimulating hormone (FSH) levels (>40 IU/L), which accounts for one major cause of female infertility[1,2]. For most patients presenting with POI, the cause remains unexplained[4]. Substantial evidence has revealed that DNA damage in our bodies is one of the leading causes for diseases such as tumor, neurodegenerative disorder, and immune deficiency[7]. Every cell generates up to 105 DNA lesions per day that are induced by exogenous physical agents, spontaneous chemical reactions, and products of endogenous metabolism[8]. Most of the damages including crosslinks, base mismatches, single strand breaks, and double-strand breaks (DSBs) could be sensed and fixed

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Conclusion