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A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice

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Abstract

Reduced fertility is a common clinical feature of the individuals with Fanconi anemia (FA), a rare autosomal recessive disorder due to deficiency in FA pathway during DNA repair. Our previous study reported that the heterozygous pathogenic variants in FANCA (Fanconi anemia complementation group A) induced premature ovarian insufficiency (POI). However, the genotype–phenotype correlation in POI caused by FANCA variants remains considerably uncertain. Herein, a heterozygous non-frameshift Fanca-mutated mouse strain (Fanca+/hypo) carrying a 9-bp deletion (c.3581del9, p.QEA1194-1196del) was generated. The mutant mice exhibited slightly decreased Fanca protein level in ovaries, suggesting the non-frameshift deletion mutant is hypomorphic. Female fertility test showed decreased number of litters, litter sizes and prolonged litter interval time in the female Fanca+/hypo mice compared to wild-type mice. Follicle counting revealed a consistent decreasing pattern of follicle numbers in Fanca+/hypo females compared to that in wild-type mice with aging. Furthermore, embryonic fibroblasts of Fanca+/hypo mice were hyper-responsive to Mitomycin C in vitro, demonstrating a partial loss of function of this hypomorphic Fanca mutant in DNA repair. Collectively, our experimental observations suggest that the hypomorphic Fanca allele is sufficient to reduce female fertility in mice, providing new insights into the genetic counseling of FANCA variants in subfertile women.

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Acknowledgements

We thank Professor Chengjian Zheng (The Second Military Medical University, China) for the kind help in mouse study.

Funding

This work was supported by National Key Research and Development Program of China (2017YFC1001100 and 2016YFC1000600), National Natural Science Foundation of China (31625015 and 31521003), Shanghai Medical Center of Key Programs for Female Reproductive Diseases (2017ZZ01016) and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).

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Author notes

  1. Yuncheng Pan, Xi Yang and Feng Zhang contributed equally to this work.

Authors and Affiliations

  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

    Yuncheng Pan, Xi Yang, Feng Zhang, Siyuan Chen, Zixue Zhou, Lingyue Shang, Jialin Yang, Guoqing Li, Yingchen Wang, Li Jin & Yanhua Wu

  2. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China

    Feng Zhang & Yanhua Wu

  3. First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei, 230027, Anhui, China

    Hao Yin, Hui Ma & Qinghua Shi

  4. National Demonstration Center for Experimental Biology Education, School of Life Sciences, Fudan University, Shanghai, 200433, China

    Yanhua Wu

Authors
  1. Yuncheng Pan
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  2. Xi Yang
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Contributions

YWu, QS and FZ designed the study. YP, XY, SC, ZZ, HY, HM, LS, JY, GL and YWa conducted experiments. YP, XY, LJ, FZ, QS and YWu analyzed data. YP, XY, FZ and YWu wrote the manuscript. FZ, QS and YWu supervised the study.

Corresponding authors

Correspondence to Qinghua Shi or Yanhua Wu.

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The authors declare no conflicts of interest.

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This work was accomplished with the approval of the Ethics Committee at School of Life Sciences, Fudan University.

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Not commissioned; externally peer reviewed.

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Communicated by Stefan Hohmann.

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Pan, Y., Yang, X., Zhang, F. et al. A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice. Mol Genet Genomics 296, 103–112 (2021). https://doi.org/10.1007/s00438-020-01730-5

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  • DOI: https://doi.org/10.1007/s00438-020-01730-5

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