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Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages

BACKGROUND: Oocyte maturation arrest results in female infertility and the genetic etiology of this phenotype remains largely unknown. Previous studies have proven that cyclins play a significant role in the cell cycle both in meiosis and mitosis. Cyclin B3 (CCNB3) is one of the members of the cycli...

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Autores principales: Wang, Congjing, Chen, Meng Xi, Zhang, Yuan, Bai, Xue, Cao, Qiqi, Han, Jian, Zhang, Nana, Zhao, Chun, Ling, Xiufeng, Rui, Ximan, Guan, Yichun, Zhang, Junqiang, Huo, Ran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463413/
https://www.ncbi.nlm.nih.gov/pubmed/37635245
http://dx.doi.org/10.1186/s13048-023-01229-8
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author Wang, Congjing
Chen, Meng Xi
Zhang, Yuan
Bai, Xue
Cao, Qiqi
Han, Jian
Zhang, Nana
Zhao, Chun
Ling, Xiufeng
Rui, Ximan
Guan, Yichun
Zhang, Junqiang
Huo, Ran
author_facet Wang, Congjing
Chen, Meng Xi
Zhang, Yuan
Bai, Xue
Cao, Qiqi
Han, Jian
Zhang, Nana
Zhao, Chun
Ling, Xiufeng
Rui, Ximan
Guan, Yichun
Zhang, Junqiang
Huo, Ran
author_sort Wang, Congjing
collection PubMed
description BACKGROUND: Oocyte maturation arrest results in female infertility and the genetic etiology of this phenotype remains largely unknown. Previous studies have proven that cyclins play a significant role in the cell cycle both in meiosis and mitosis. Cyclin B3 (CCNB3) is one of the members of the cyclin family and its function in human oocyte maturation is poorly understood. METHODS: 118 infertile patients were recruited and WES was performed for 68 independent females that experienced oocyte maturation arrest. Four mutations in CCNB3 were found and effects of these mutations were validated by Sanger sequencing and in vitro functional analyses. RESULTS: We found these mutations altered the location of cyclin B3 which affected the function of cyclin dependent kinase 1 (CDK1) and led to mouse oocyte arrested at germinal vesicle (GV) stage. And then, low CDK1 activity influenced the degradation of cadherin 1 (CDH1) and the accumulation of cell division cycle 20 (CDC20) which are two types of anaphase-promoting complex/cyclosome (APC/C) activators and act in different stages of the cell cycle. Finally, APC/C activity was downregulated due to insufficient CDC20 level and resulted in oocyte metaphase I (MI) arrest. Moreover, we also found that the addition of PP1 inhibitor Okadic acid and CDK1 inhibitor Roscovitine at corresponding stages during oocyte in vitro maturation (IVM) significantly improved the maturation rates in CCNB3 mutant cRNAs injected oocytes. The above experiments were performed in mouse oocytes. CONCLUSION: Here, we report five independent patients in which mutations in CCNB3 may be the cause of oocyte maturation arrest. Our findings shed lights on the critical role of CCNB3 in human oocyte maturation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-023-01229-8.
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spelling pubmed-104634132023-08-30 Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages Wang, Congjing Chen, Meng Xi Zhang, Yuan Bai, Xue Cao, Qiqi Han, Jian Zhang, Nana Zhao, Chun Ling, Xiufeng Rui, Ximan Guan, Yichun Zhang, Junqiang Huo, Ran J Ovarian Res Research BACKGROUND: Oocyte maturation arrest results in female infertility and the genetic etiology of this phenotype remains largely unknown. Previous studies have proven that cyclins play a significant role in the cell cycle both in meiosis and mitosis. Cyclin B3 (CCNB3) is one of the members of the cyclin family and its function in human oocyte maturation is poorly understood. METHODS: 118 infertile patients were recruited and WES was performed for 68 independent females that experienced oocyte maturation arrest. Four mutations in CCNB3 were found and effects of these mutations were validated by Sanger sequencing and in vitro functional analyses. RESULTS: We found these mutations altered the location of cyclin B3 which affected the function of cyclin dependent kinase 1 (CDK1) and led to mouse oocyte arrested at germinal vesicle (GV) stage. And then, low CDK1 activity influenced the degradation of cadherin 1 (CDH1) and the accumulation of cell division cycle 20 (CDC20) which are two types of anaphase-promoting complex/cyclosome (APC/C) activators and act in different stages of the cell cycle. Finally, APC/C activity was downregulated due to insufficient CDC20 level and resulted in oocyte metaphase I (MI) arrest. Moreover, we also found that the addition of PP1 inhibitor Okadic acid and CDK1 inhibitor Roscovitine at corresponding stages during oocyte in vitro maturation (IVM) significantly improved the maturation rates in CCNB3 mutant cRNAs injected oocytes. The above experiments were performed in mouse oocytes. CONCLUSION: Here, we report five independent patients in which mutations in CCNB3 may be the cause of oocyte maturation arrest. Our findings shed lights on the critical role of CCNB3 in human oocyte maturation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-023-01229-8. BioMed Central 2023-08-28 /pmc/articles/PMC10463413/ /pubmed/37635245 http://dx.doi.org/10.1186/s13048-023-01229-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Congjing
Chen, Meng Xi
Zhang, Yuan
Bai, Xue
Cao, Qiqi
Han, Jian
Zhang, Nana
Zhao, Chun
Ling, Xiufeng
Rui, Ximan
Guan, Yichun
Zhang, Junqiang
Huo, Ran
Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages
title Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages
title_full Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages
title_fullStr Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages
title_full_unstemmed Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages
title_short Mutations in CCNB3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant CDK1 activity and APC/C activity at different stages
title_sort mutations in ccnb3 affect its location thus causing a multiplicity of phenotypes in human oocytes maturation by aberrant cdk1 activity and apc/c activity at different stages
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10463413/
https://www.ncbi.nlm.nih.gov/pubmed/37635245
http://dx.doi.org/10.1186/s13048-023-01229-8
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