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Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest

  • Lin Zhao
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China

    NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
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  • Qun Li
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China

    Human Phenome Institute, Fudan University, Shanghai, China
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  • Yanping Kuang
    Affiliations
    Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Peng Xu
    Affiliations
    Hainan Jinghua Hejing Hospital for Reproductive Medicine, Haikou, China
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  • Xiaoxi Sun
    Affiliations
    Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
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  • Qingxia Meng
    Affiliations
    Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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  • Wenjing Wang
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Yang Zeng
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Biaobang Chen
    Affiliations
    NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
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  • Jing Fu
    Affiliations
    Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
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  • Jie Dong
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Jiawei Zhu
    Affiliations
    Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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  • Yuxi Luo
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Hao Gu
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Caihong Li
    Affiliations
    Shenyang Jinghua Hospital, Liaoning, China
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  • Chunyi Li
    Affiliations
    Shenyang Jinghua Hospital, Liaoning, China
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  • Ling Wu
    Affiliations
    Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Xiaoyan Mao
    Affiliations
    Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China
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  • Huizhen Fan
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Ruyi Liu
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Zhihua Zhang
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Qiaoli Li
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Jing Du
    Affiliations
    NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
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  • Lin He
    Affiliations
    Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
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  • Li Jin
    Affiliations
    State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
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  • Lei Wang
    Correspondence
    Correspondence and requests for materials should be addressed to Lei Wang and Qing Sang, Fudan University, Institutes of Biomedical Sciences, Dong’an Road No 131, Shanghai, China 200032
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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  • Qing Sang
    Correspondence
    Correspondence and requests for materials should be addressed to Lei Wang and Qing Sang, Fudan University, Institutes of Biomedical Sciences, Dong’an Road No 131, Shanghai, China 200032
    Affiliations
    Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
    Search for articles by this author
Published:August 27, 2022DOI:https://doi.org/10.1016/j.gim.2022.07.027

      Abstract

      Purpose

      The genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test.

      Methods

      Through comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes.

      Results

      A total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg138∗], c.282C>A [p.Cys94∗]; c.257dup [p.Tyr86∗]; and c.180del, [p.Ser61Profs∗30]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes.

      Conclusion

      By combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.

      Keywords

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