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Purpose <p>Asthenoteratozoospermia represents a leading cause of idiopathic male infertility, characterized by diminished sperm motility and aberrant morphology. Testis-expressed protein 44 (<i>Tex44</i>) is essential for sperm flagellar development in mice, yet its pathogenic contribution to human asthenoteratozoospermia and clinical translational relevance remain largely undefined. This study aimed to characterize the role of TEX44 in sperm structure and function, identify pathogenic TEX44 variants in infertile men, and evaluate intracytoplasmic sperm injection (ICSI) as a fertility-rescue strategy.</p> Methods <p>A <i>Tex44</i>-knockout (<i>Tex44</i><sup>⁻/⁻</sup>) mouse model was generated using CRISPR/Cas9. Sperm parameters were analyzed by computer-assisted sperm analysis (CASA), coupled with ultrastructural, transcriptomic, and functional fertility assays (in vivo fertilization, IVF, ICSI). Whole-exome sequencing (WES) was performed in 535 well-phenotyped infertile men, and candidate TEX44 variants were verified by Sanger sequencing. Protein structure prediction and clinical ICSI outcome analysis were also performed.</p> Results <p><i>Tex44</i><sup>⁻/⁻</sup> mice displayed asthenoteratozoospermia, marked by disrupted axonemal 9 + 2 microtubule organization, defective mitochondrial sheath assembly, and compromised fertility, all of which were effectively rescued by ICSI. Transcriptomic profiling demonstrated dysregulation of pathways governing flagellar structure and mitochondrial function. In humans, three pathogenic TEX44 variants were identified in seven affected individuals. All patients presented with severe semen abnormalities. ICSI resulted in favorable reproductive outcomes, including healthy live births.</p> Conclusions <p><i>Tex44</i> deficiency causes asthenoteratozoospermia by impairing sperm axonemal integrity and mitochondrial sheath assembly. Pathogenic TEX44 variants are associated with human asthenoteratozoospermia, and ICSI serves as an effective therapeutic intervention for affected patients. These findings establish TEX44 as a novel diagnostic biomarker, broaden the genetic architecture of male infertility, and strengthen the translational bridge between basic science and clinical reproductive care.</p>

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TEX44 deficiency induces asthenoteratozoospermia by disrupting sperm axonemal integrity and mitochondrial sheath assembly, and ICSI enables successful fertility rescue

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Qi-qi Chen,
  • Xin Qiu,
  • Yu-Jun Liu,
  • Yu-Jiao Dang,
  • Ping Liu,
  • Rong Li,
  • Xu Zhi,
  • Xin-jie Zhuang

摘要

Purpose

Asthenoteratozoospermia represents a leading cause of idiopathic male infertility, characterized by diminished sperm motility and aberrant morphology. Testis-expressed protein 44 (Tex44) is essential for sperm flagellar development in mice, yet its pathogenic contribution to human asthenoteratozoospermia and clinical translational relevance remain largely undefined. This study aimed to characterize the role of TEX44 in sperm structure and function, identify pathogenic TEX44 variants in infertile men, and evaluate intracytoplasmic sperm injection (ICSI) as a fertility-rescue strategy.

Methods

A Tex44-knockout (Tex44⁻/⁻) mouse model was generated using CRISPR/Cas9. Sperm parameters were analyzed by computer-assisted sperm analysis (CASA), coupled with ultrastructural, transcriptomic, and functional fertility assays (in vivo fertilization, IVF, ICSI). Whole-exome sequencing (WES) was performed in 535 well-phenotyped infertile men, and candidate TEX44 variants were verified by Sanger sequencing. Protein structure prediction and clinical ICSI outcome analysis were also performed.

Results

Tex44⁻/⁻ mice displayed asthenoteratozoospermia, marked by disrupted axonemal 9 + 2 microtubule organization, defective mitochondrial sheath assembly, and compromised fertility, all of which were effectively rescued by ICSI. Transcriptomic profiling demonstrated dysregulation of pathways governing flagellar structure and mitochondrial function. In humans, three pathogenic TEX44 variants were identified in seven affected individuals. All patients presented with severe semen abnormalities. ICSI resulted in favorable reproductive outcomes, including healthy live births.

Conclusions

Tex44 deficiency causes asthenoteratozoospermia by impairing sperm axonemal integrity and mitochondrial sheath assembly. Pathogenic TEX44 variants are associated with human asthenoteratozoospermia, and ICSI serves as an effective therapeutic intervention for affected patients. These findings establish TEX44 as a novel diagnostic biomarker, broaden the genetic architecture of male infertility, and strengthen the translational bridge between basic science and clinical reproductive care.