Bi-allelic Missense Pathogenic Variants in TRIP13 Cause Female Infertility Characterized by Oocyte Maturation Arrest

Am J Hum Genet. 2020 Jul 2;107(1):15-23. doi: 10.1016/j.ajhg.2020.05.001.

Zhihua Zhang ¹, Bin Li ², Jing Fu ³, Rong Li ⁴, Feiyang Diao ⁵, Caihong Li ⁶, Biaobang Chen ⁷, Jing Du ⁷, Zhou Zhou ¹, Jian Mu ¹, Zheng Yan ², Ling Wu ², Shuai Liu ⁸, Wenjing Wang ¹, Lin Zhao ¹, Jie Dong ¹, Lin He ⁹, Xiaozhen Liang ⁸, Yanping Kuang ², Xiaoxi Sun ³, Qing Sang ¹⁰, Lei Wang ¹¹

Affiliations

1 Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, the Ministry of Science and Technology, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China.
2 Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai 200011, China.
3 Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
4 Reproductive Medicine Center, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China.
5 The State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
6 Assisted Reproductive Technology Laboratory, Shenyang Jinghua Hospitals, Shenyang, Liaoning 110005, China.
7 National Health Commission Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, Shanghai 200032, China.
8 Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China.
9 Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China.
10 Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, the Ministry of Science and Technology, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China. Electronic address: sangqing@fudan.edu.cn.
11 Institute of Pediatrics, Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, the Ministry of Science and Technology, the Institutes of Biomedical Sciences, and the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Shanghai Center for Women and Children's Health, Shanghai 200062, China. Electronic address: wangleiwanglei@fudan.edu.cn.

PMID: 32473092 DOI: 10.1016/j.ajhg.2020.05.001

Abstract

Normal oocyte meiosis is a prerequisite for successful human reproduction, and abnormalities in the process will result in infertility. In 2016, we identified mutations in TUBB8 as responsible for human oocyte meiotic arrest. However, the underlying genetic factors for most affected individuals remain unknown. TRIP13, encoding an AAA-ATPase, is a key component of the spindle assembly checkpoint, and recurrent homozygous nonsense variants and a splicing variant in TRIP13 are reported to cause Wilms tumors in children. In this study, we identified homozygous and compound heterozygous missense pathogenic variants in TRIP13 responsible for female infertility mainly characterized by oocyte meiotic arrest in five individuals from four independent families. Individuals from three families suffered from oocyte maturation arrest, whereas the individual from the fourth family had abnormal zygote cleavage. All displayed only the infertility phenotype without Wilms tumors or any Other abnormalities. In vitro and in vivo studies showed that the identified variants reduced the protein abundance of TRIP13 and caused its downstream molecule, HORMAD2, to accumulate in HeLa cells and in proband-derived lymphoblastoid cells. The chromosome mis-segregation assay showed that variants did not have any effects on mitosis. Injecting TRIP13 cRNA into oocytes from one affected individual was able to rescue the phenotype, which has implications for future therapeutic treatments. This study reports pathogenic variants in TRIP13 responsible for oocyte meiotic arrest, and it highlights the pivotal but different roles of TRIP13 in meiosis and mitosis. These findings also indicate that different dosage effects of mutant TRIP13 might result in two distinct human diseases.

Keywords

TRIP13; female infertility; missense mutation; oocyte maturation arrest.

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