Novel PLCZ1 compound heterozygous mutations indicate gene dosage effect involved in TFF after ICSI

in Reproduction
Authors:
Qing Li Q Li, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University West China Second University Hospital, Chengdu, China

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Juncen Guo J Guo, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University West China Second University Hospital, Chengdu, China

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Gelin Huang G Huang, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University West China Second University Hospital, Chengdu, China

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Nan Wu N Wu, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China

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Su Chen S Chen, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China

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Jing Dai J Dai, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China

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Xueguang Zhang X Zhang, Department of Obstetrics/Gynecology, Sichuan University West China Second University Hospital, chengdu, China

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Guohui Zhang G Zhang, Key Laboratory of Reproductive Medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, China

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Weiwei Zhi W Zhi, Key Laboratory of reproductive medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, China

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Jierui Yan J Yan, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University West China Second University Hospital, Chengdu, China

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Rui Zheng R Zheng, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education,, Sichuan University West China Second University Hospital, Chengdu, China

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Fei Yan F Yan, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University West China Second University Hospital, Chengdu, China

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Zheng Yan Z Yan, Department of Assisted Reproduction, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China

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Ling Wu L Wu, Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China

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Sixian Wu S Wu, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecolo, Sichuan University West China Second University Hospital, Chengdu, China

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Zhiliang Ji Z Ji, State Key Laboratory of Cellular Stress Biology, School of Life Sciences, National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, China

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Jiuzhi Zeng J Zeng, Key Laboratory of reproductive medicine, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, China

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Ge Lin G Lin, Central South University, Institute of Reproductive and Stem Cell Engineering, Changsha, China

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Bin Li B Li, Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Center for Specialty Strategy Research of Shanghai Jiao Tong University China Hospital Development Institute, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China

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Wenming Xu W Xu, Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, Sichuan University West China Second University Hospital, Chengdu, China

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Correspondence: Wenming Xu, Email: xuwenming@scu.edu.cn
DOI:
https://doi.org/10.1530/REP-23-0466
Volume/Issue:
Accepted Manuscripts
Article ID:
REP-23-0466
Article Type:
Research Article
Online Publication Date:
01 Jul 2024
Copyright:
© 2024 The authors 2024
Open access

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Oocyte activation failure, one of the main factors of total fertilization failure (TFF) after ICSI, could be induced by abnormal calcium oscillations. Phospholipase C zeta (PLCζ), a sperm factor, was associated with Ca2+ oscillations in oocytes of mammals. To date, only a limited number of mutations in PLCZ1 (the gene encodes PLCζ) have been linked to TFF demonstrated by the observed reduction in protein levels or activity. In this study, males with normozoospermic sperm suffering TFF after ICSI and their families were recruited. Firstly, mutations in the PLCZ1 sequence were identified by Whole exome sequencing and validated by Sanger sequencing. Then the transcript and protein levels and locations of PLCZ1/PLCζ in sperms of patients were studied followed by in vitro function analysis and in silico analysis to investigate the function-structure correlation of mutations identified in PLCZ1 through Western blotting, Immunofluorescence, RT-qPCR and Molecular Simulation. Ca2+ oscillations were detected after cRNA microinjection with MⅡ mouse oocyte to investigate the calcium oscillations of abnormal PLCζ. Five variants in compound heterozygosity were identified including five new mutations and three-reported mutations which were located across the main domains of PLCζ, except the EF hands domain. The transcript and protein levels were decreased among all the mutations identified in PLCZ1 at different degrees when transfected with HEK293T cells. Among these mutations, M138V and R391* of PLCζ could not trigger normal Ca2+ oscillations. In case 5, an abnormal location in the head of sperm and a higher expression of PLCζ in the sperm were found.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899