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Hum Genet. 2019 Sep 18. doi: 10.1007/s00439-019-02059-9. [Epub ahead of print]

Rare variants in FANCA induce premature ovarian insufficiency.

Author information

1
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic, Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China.
2
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
3
Center of Reproductive Medicine, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
4
The Research Center for Medical Genomics, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, College of Basic Medical Science, China Medical University, Shenyang, 110001, China.
5
The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei, 230027, China.
6
Shanghai Ji Ai Genetic and IVF Institute, Fudan University, Shanghai, 200011, China.
7
The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei, 230027, China. qshi@ustc.edu.cn.
8
Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic, Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China. yanhuawu@fudan.edu.cn.
9
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China. yanhuawu@fudan.edu.cn.
10
National Demonstration Center for Experimental Biology Education, School of Life Sciences, Fudan University, Shanghai, 200433, China. yanhuawu@fudan.edu.cn.

Abstract

Premature ovarian insufficiency (POI) is a major cause of reduced female fertility and affects approximately 1% women under 40 years of age. Recent advances emphasize the genetic heterogeneity of POI. Fanconi anemia (FA) genes, traditionally known for their essential roles in DNA repair and cytogenetic instability, have been demonstrated to be involved in meiosis and germ cell development. Here, we conducted whole-exome sequencing (WES) in 50 Han Chinese female patients with POI. Rare missense variants were identified in FANCA (Fanconi anemia complementation group A): c.1772G > A (p.R591Q) and c.3887A > G (p.E1296G). Both variants are heterozygous in the patients and very rare in the human population. In vitro functional studies further demonstrated that these two missense variants of FANCA exhibited reduced protein expression levels compared with the wild type, suggesting the partial loss of function. Moreover, mono-ubiquitination levels of FANCD2 upon mitomycin C stimulation were significantly reduced in cells overexpressing FANCA variants. Furthermore, a loss-of-function mutation of Fanca was generated in C57BL/6 mice for in vivo functional assay. Consistently, heterozygous mutated female mice (Fanca+/-) showed reduced fertility and declined numbers of follicles with aging when compared with the wild-type female mice. Collectively, our results suggest that heterozygous pathogenic variants in FANCA are implicated in non-syndromic POI in Han Chinese women, provide new insights into the molecular mechanisms of POI and highlight the contribution of FANCA variants in female subfertility.

PMID:
31535215
DOI:
10.1007/s00439-019-02059-9

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