Ruiqi Li, Mei Mei, Ling Zhou, Haijing Zhao, Min Yang, Yingshi Li, Xiaoli Chen, Wenjun Wang, Ping Yuan
{"title":"Biallelic Recessive Mutations in TLE6 and NLRP5 Cause Female Infertility Characterized by Human Early Embryonic Arrest","authors":"Ruiqi Li, Mei Mei, Ling Zhou, Haijing Zhao, Min Yang, Yingshi Li, Xiaoli Chen, Wenjun Wang, Ping Yuan","doi":"10.1155/2024/9278518","DOIUrl":null,"url":null,"abstract":"<div>\n <p>Preimplantation embryonic developmental arrest (EDA) is a common cause of unexplained female infertility. Genetic factors are believed to be one of the primary causes contributing to EDA. In this study, we identify four novel compound heterozygous mutations in <i>TLE6</i> and <i>NLRP5</i>, in two infertile female patients experiencing recurrent EDA, using whole-exome sequencing. Functional analysis revealed that the two splicing mutations in <i>TLE6</i> (c.541+2dupT) and <i>NLRP5</i> (c.2957+4A>G) resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. <i>In vitro</i> experiments further validated that a missense mutation in <i>NLRP5</i> led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells. Immunofluorescence analysis confirmed the decay of the expression of TLE6 protein. Additionally, RNA sequencing results revealed significantly higher expression levels of some maternal genes in mutated embryos with <i>TLE6</i> mutations, possibly suggesting the disrupted clearance of maternal mRNA and the failure of embryo genome activation. These results highlight the role of biallelic recessive effects associated with <i>TLE6</i> and <i>NLRP5</i> variants in embryonic development, thereby widening the scope of the genetic landscape.</p>\n </div>","PeriodicalId":3,"journal":{"name":"ACS Applied Electronic Materials","volume":null,"pages":null},"PeriodicalIF":4.3000,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/9278518","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Electronic Materials","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/2024/9278518","RegionNum":3,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, ELECTRICAL & ELECTRONIC","Score":null,"Total":0}
引用次数: 0
Abstract
Preimplantation embryonic developmental arrest (EDA) is a common cause of unexplained female infertility. Genetic factors are believed to be one of the primary causes contributing to EDA. In this study, we identify four novel compound heterozygous mutations in TLE6 and NLRP5, in two infertile female patients experiencing recurrent EDA, using whole-exome sequencing. Functional analysis revealed that the two splicing mutations in TLE6 (c.541+2dupT) and NLRP5 (c.2957+4A>G) resulted in aberrant RNA splicing, leading to abnormal truncations of the corresponding proteins. In vitro experiments further validated that a missense mutation in NLRP5 led to increased mRNA and protein expression levels compared to wild type, when transfected into HEK293T cells. Immunofluorescence analysis confirmed the decay of the expression of TLE6 protein. Additionally, RNA sequencing results revealed significantly higher expression levels of some maternal genes in mutated embryos with TLE6 mutations, possibly suggesting the disrupted clearance of maternal mRNA and the failure of embryo genome activation. These results highlight the role of biallelic recessive effects associated with TLE6 and NLRP5 variants in embryonic development, thereby widening the scope of the genetic landscape.