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Purpose <p>To identify the disease-causing gene behind infertile couples with female infertility and abnormal fertilization.</p> Methods <p>Whole-exome sequencing and Sanger sequencing were used to identify variants in disease-causing genes in 119 infertile couples with abnormal fertilization. Molecular modeling and functional analysis were used to evaluate the pathogenic effects of the variants.</p> Results <p>We identified one homozygous <i>ASTL</i> variant and three homozygous <i>WEE2</i> variants from four affected individuals. Among them, <i>WEE2</i> variants c.1006<sub>-</sub>1007insTA (p.His337Tyrfs*24) and c.585G &gt; C (p.Lys195Asn) have been previously reported. Structural modeling indicated that the novel <i>ASTL</i> variant c.643G &gt; A (p.Glu215Lys) disrupted the hydrogen bond with Gly-213, while the novel <i>WEE2</i> variant c.791C &gt; T (p.Ala264Val) significantly decreased tyrosine 15 phosphorylation on Cdc2 and reduced pronucleus formation rate in vitro<i>.</i> In addition, intracytoplasmic sperm injection with assisted oocyte activation (ICSI-AOA) can prevent polyspermy in oocytes with <i>ASTL</i> c.643G &gt; A (p.Glu215Lys) variant and can assist patients in delivering a girl.</p> Conclusions <p>We identified novel homozygous variants in <i>ASTL</i> and <i>WEE2</i>, and functional analysis confirmed the pathogenicity of these variants. In addition, ICSI-AOA rescued the polyspermy phenotype in patients with <i>ASTL</i> c.643G &gt; A (p.Glu215Lys) variant. Our findings further reveal the important role of <i>ASTL</i> and <i>WEE2</i> in female reproduction and expand the mutational spectrum of the abnormal fertilization related genes <i>ASTL</i> and <i>WEE2.</i></p>

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Novel homozygous variants in ASTL and WEE2 responsible for female infertility characterized by abnormal fertilization

  • 期刊论文

  • 发表日期：

    2025年8月19日

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  • Siyuan Xie,
  • Meiling Zhang,
  • Fengyan Wu,
  • Ran Yu,
  • Jing Fu,
  • Rong Shi,
  • Qiaoli Li,
  • Biaobang Chen,
  • Juanzi Shi,
  • Tianyu Wu,
  • Xiaoxi Sun,
  • Qing Sang,
  • Lei Wang,
  • Weijie Wang,
  • Jian Mu

摘要

Purpose

To identify the disease-causing gene behind infertile couples with female infertility and abnormal fertilization.

Methods

Whole-exome sequencing and Sanger sequencing were used to identify variants in disease-causing genes in 119 infertile couples with abnormal fertilization. Molecular modeling and functional analysis were used to evaluate the pathogenic effects of the variants.

Results

We identified one homozygous ASTL variant and three homozygous WEE2 variants from four affected individuals. Among them, WEE2 variants c.1006-1007insTA (p.His337Tyrfs*24) and c.585G > C (p.Lys195Asn) have been previously reported. Structural modeling indicated that the novel ASTL variant c.643G > A (p.Glu215Lys) disrupted the hydrogen bond with Gly-213, while the novel WEE2 variant c.791C > T (p.Ala264Val) significantly decreased tyrosine 15 phosphorylation on Cdc2 and reduced pronucleus formation rate in vitro. In addition, intracytoplasmic sperm injection with assisted oocyte activation (ICSI-AOA) can prevent polyspermy in oocytes with ASTL c.643G > A (p.Glu215Lys) variant and can assist patients in delivering a girl.

Conclusions

We identified novel homozygous variants in ASTL and WEE2, and functional analysis confirmed the pathogenicity of these variants. In addition, ICSI-AOA rescued the polyspermy phenotype in patients with ASTL c.643G > A (p.Glu215Lys) variant. Our findings further reveal the important role of ASTL and WEE2 in female reproduction and expand the mutational spectrum of the abnormal fertilization related genes ASTL and WEE2.