Biallelic Recessive Mutations in TLE6 and NLRP5 Cause Female Infertility Characterized by Human Early Embryonic Arrest

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
Ruiqi Li, Mei Mei, Ling Zhou, Haijing Zhao, Min Yang, Yingshi Li, Xiaoli Chen, Wenjun Wang, Ping Yuan
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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.

Abstract Image

TLE6和NLRP5的双侧隐性突变导致以人类胚胎早期停滞为特征的女性不孕症
胚胎植入前发育停滞(EDA)是导致不明原因的女性不孕症的常见原因。遗传因素被认为是导致 EDA 的主要原因之一。在本研究中,我们利用全外显子组测序技术,在两名反复出现 EDA 的不孕女性患者中发现了 TLE6 和 NLRP5 的四个新型复合杂合突变。功能分析显示,TLE6(c.541+2dupT)和NLRP5(c.2957+4A>G)的两个剪接突变导致RNA剪接异常,从而导致相应蛋白的异常截断。体外实验进一步验证了 NLRP5 的错义突变导致转染 HEK293T 细胞后的 mRNA 和蛋白质表达水平高于野生型。免疫荧光分析证实了 TLE6 蛋白表达的衰减。此外,RNA测序结果显示,在TLE6突变的胚胎中,一些母体基因的表达水平明显较高,这可能表明母体mRNA的清除被破坏,胚胎基因组激活失败。这些结果突显了与 TLE6 和 NLRP5 变体相关的双倍隐性效应在胚胎发育中的作用,从而拓宽了遗传学的研究范围。
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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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