Scholarlink

<p>Oocyte and early embryo competence defects (OECD) are a kind of Mendelian genetic disorder. While numerous pathogenic variants have been identified, the underlying molecular mechanisms remain largely elusive. In this study, through whole-exome sequencing of infertile patients, we identified five novel biallelic mutations in <i>YTHDC2</i>, a locus previously implicated in primary ovarian insufficiency, in four families with OECD. Of note, two affected individuals presented with diminished ovarian reserve. To delineate the functional consequences of these variants, we overexpressed human mutant <i>YTHDC2</i> in mouse growing oocytes at the GO2 stage (50–55&#xa0;μm in diameter) with high <i>Ythdc2</i> expression, and performed transcriptomic profiling. In parallel, we conducted single-cell RNA sequencing of human preimplantation embryo carrying <i>YTHDC2</i> mutations. By integrating mouse <i>Ythdc2</i> iCLIP-seq data, transcriptomes of GO2 oocytes, and human embryonic single-cell data, we demonstrate that <i>YTHDC2</i> mutations disrupt RNA homeostasis, leading to progressive functional abnormalities during oocyte and early embryonic development. Furthermore, mutant <i>YTHDC2</i> overexpressed in mouse zygotes significantly compromised early embryonic development, characterized by a marked reduction in blastocyst formation rates. Our study identifies <i>YTHDC2</i> as a critical regulator of oocyte and early embryonic development and provides a novel target for clinical genetic diagnosis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Human YTHDC2 mutations disturb RNA homeostasis of oocytes and early embryos

  • 期刊论文

  • 发表日期：

    2026年3月21日

查看全文
  • Wei Su,
  • Yang Wang,
  • Jiaqi Sun,
  • Changlong Zhang,
  • Changjian Yin,
  • Ying Cui,
  • Xiaolei Chen,
  • Bohan Yang,
  • Shigang Zhao,
  • Keliang Wu,
  • Ge Lin,
  • Zi-Jiang Chen,
  • Wei Zheng,
  • Honghui Zhang,
  • Han Zhao

摘要

Oocyte and early embryo competence defects (OECD) are a kind of Mendelian genetic disorder. While numerous pathogenic variants have been identified, the underlying molecular mechanisms remain largely elusive. In this study, through whole-exome sequencing of infertile patients, we identified five novel biallelic mutations in YTHDC2, a locus previously implicated in primary ovarian insufficiency, in four families with OECD. Of note, two affected individuals presented with diminished ovarian reserve. To delineate the functional consequences of these variants, we overexpressed human mutant YTHDC2 in mouse growing oocytes at the GO2 stage (50–55 μm in diameter) with high Ythdc2 expression, and performed transcriptomic profiling. In parallel, we conducted single-cell RNA sequencing of human preimplantation embryo carrying YTHDC2 mutations. By integrating mouse Ythdc2 iCLIP-seq data, transcriptomes of GO2 oocytes, and human embryonic single-cell data, we demonstrate that YTHDC2 mutations disrupt RNA homeostasis, leading to progressive functional abnormalities during oocyte and early embryonic development. Furthermore, mutant YTHDC2 overexpressed in mouse zygotes significantly compromised early embryonic development, characterized by a marked reduction in blastocyst formation rates. Our study identifies YTHDC2 as a critical regulator of oocyte and early embryonic development and provides a novel target for clinical genetic diagnosis.