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Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest

The subcortical maternal complex (SCMC), composed of several maternal‐effect genes, is vital for the development of oocytes and early embryos. Variants of SCMC‐encoding genes (NLRP2, NLRP5, TLE6, PADI6, and KHDC3L, but not OOEP and ZBED3) are associated with human oocyte maturation dysfunction, fert...

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Autores principales: Tong, Xiaomei, Jin, Jiamin, Hu, Zhanhong, Zhang, Yingyi, Fan, Heng‐Yu, Zhang, Yin‐Li, Zhang, Songying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087254/
https://www.ncbi.nlm.nih.gov/pubmed/35946397
http://dx.doi.org/10.1002/humu.24448
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author Tong, Xiaomei
Jin, Jiamin
Hu, Zhanhong
Zhang, Yingyi
Fan, Heng‐Yu
Zhang, Yin‐Li
Zhang, Songying
author_facet Tong, Xiaomei
Jin, Jiamin
Hu, Zhanhong
Zhang, Yingyi
Fan, Heng‐Yu
Zhang, Yin‐Li
Zhang, Songying
author_sort Tong, Xiaomei
collection PubMed
description The subcortical maternal complex (SCMC), composed of several maternal‐effect genes, is vital for the development of oocytes and early embryos. Variants of SCMC‐encoding genes (NLRP2, NLRP5, TLE6, PADI6, and KHDC3L, but not OOEP and ZBED3) are associated with human oocyte maturation dysfunction, fertilization failure, and early embryonic arrest. In this study, we enrolled 118 Chinese patients who experienced recurrent preimplantation embryonic arrest during assisted reproductive technology treatments and performed whole‐exome sequencing. We discovered compound heterozygous missense variants (c.110G>C and c.109C>G) in the OOEP gene in one patient who experienced recurrent preimplantation embryonic arrest. Arrested embryos from this affected patient were analyzed by single‐cell RNA sequencing, which showed a downregulated transcriptome. In addition, six novel NLRP5 variants (c.971T>A, c.3341T>C, c.1575_1576delAG, c.1830_1831delGT, c.1202C>T, and c.2378T>G) were identified in four patients with arrested and severely fragmented embryos. These suspicious mutations were examined by in vitro studies in HEK293T cells. Western blot analysis and immunofluorescence experiments showed that OOEP and partial NLRP5 mutations caused decreased protein levels. Our findings first demonstrated that biallelic variants in OOEP gene could also cause human early embryonic arrest, similar to other SCMC components. We expanded the genetic mutation spectrum of SCMC genes related to early embryogenesis in humans, especially early embryonic arrest.
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spelling pubmed-100872542023-04-12 Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest Tong, Xiaomei Jin, Jiamin Hu, Zhanhong Zhang, Yingyi Fan, Heng‐Yu Zhang, Yin‐Li Zhang, Songying Hum Mutat Research Articles The subcortical maternal complex (SCMC), composed of several maternal‐effect genes, is vital for the development of oocytes and early embryos. Variants of SCMC‐encoding genes (NLRP2, NLRP5, TLE6, PADI6, and KHDC3L, but not OOEP and ZBED3) are associated with human oocyte maturation dysfunction, fertilization failure, and early embryonic arrest. In this study, we enrolled 118 Chinese patients who experienced recurrent preimplantation embryonic arrest during assisted reproductive technology treatments and performed whole‐exome sequencing. We discovered compound heterozygous missense variants (c.110G>C and c.109C>G) in the OOEP gene in one patient who experienced recurrent preimplantation embryonic arrest. Arrested embryos from this affected patient were analyzed by single‐cell RNA sequencing, which showed a downregulated transcriptome. In addition, six novel NLRP5 variants (c.971T>A, c.3341T>C, c.1575_1576delAG, c.1830_1831delGT, c.1202C>T, and c.2378T>G) were identified in four patients with arrested and severely fragmented embryos. These suspicious mutations were examined by in vitro studies in HEK293T cells. Western blot analysis and immunofluorescence experiments showed that OOEP and partial NLRP5 mutations caused decreased protein levels. Our findings first demonstrated that biallelic variants in OOEP gene could also cause human early embryonic arrest, similar to other SCMC components. We expanded the genetic mutation spectrum of SCMC genes related to early embryogenesis in humans, especially early embryonic arrest. John Wiley and Sons Inc. 2022-08-30 2022-12 /pmc/articles/PMC10087254/ /pubmed/35946397 http://dx.doi.org/10.1002/humu.24448 Text en © 2022 The Authors. Human Mutation published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Tong, Xiaomei
Jin, Jiamin
Hu, Zhanhong
Zhang, Yingyi
Fan, Heng‐Yu
Zhang, Yin‐Li
Zhang, Songying
Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest
title Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest
title_full Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest
title_fullStr Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest
title_full_unstemmed Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest
title_short Mutations in OOEP and NLRP5 identified in infertile patients with early embryonic arrest
title_sort mutations in ooep and nlrp5 identified in infertile patients with early embryonic arrest
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10087254/
https://www.ncbi.nlm.nih.gov/pubmed/35946397
http://dx.doi.org/10.1002/humu.24448
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