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<p>Oligoasthenoteratozoospermia (OAT) is a prevalent situation of male infertility partly caused by genetic defects with largely undiscovered. To further unravel the genetic etiology of OAT, we recruited cases for whole-exome sequencing (WES) to screen candidate pathogenic mutations. Here, we identified a heterozygous missense mutation in <i>transcription factor-like 5</i> (<i>TCFL5</i>) (NM_006602.4: c.1207G &gt; A: p.E403K) from two infertile brothers born into a non-consanguineous family. <i>TCFL5</i> was previously linked to male infertility since <i>Tcfl5</i><sup>+/−</sup> male mice manifested infertile due to OAT, while <i>Tcfl5</i><sup><i>−/−</i></sup> mice could not be generated. Sperm morphological analysis of these brothers exhibited a similar OAT phenotype to <i>Tcfl5</i><sup>+/−</sup> mice. In vitro functional analysis performed to explore the pathogenicity of <i>TCFL5</i> mutation. Regardless of no significant effect on the expression of mutant TCFL5 detected by western blotting and immunofluorescence, dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function. Many crucial genes involved in spermatogenesis, such as <i>DMRT1</i>, <i>DAZL</i>, <i>SYCE1</i>, <i>SPACA1</i>, <i>CNTROB</i>, <i>IFT88</i>, <i>HOOK1</i> and <i>SPATA6</i>, occurred transcriptional abnormalities after <i>TCFL5</i> mutated. Our results showed that <i>TCFL5</i> mutation disrupted the normal transcription of spermatogenesis genes, finally resulting in male infertility raised by OAT. Our work firstly linked <i>TCFL5</i> mutation to male infertility in human, which provides a new perspective on the genetic underpinnings of OAT and a theoretical basis for clinic genetic counseling and treatment strategies selection.</p>

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A missense mutation in TCFL5 is associated with male infertility due to oligoasthenoteratozoospermia

  • 期刊论文

  • 发表日期：

    2025年7月25日

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  • Kexin Yu,
  • Wenchen Zhang,
  • Yu Wang,
  • Mingfei Xiang,
  • Na Zheng,
  • Jingjing Zhang,
  • Xiaomin Zha,
  • Zongliu Duan,
  • Fengsong Wang,
  • Yunxia Cao,
  • Fuxi Zhu

摘要

Oligoasthenoteratozoospermia (OAT) is a prevalent situation of male infertility partly caused by genetic defects with largely undiscovered. To further unravel the genetic etiology of OAT, we recruited cases for whole-exome sequencing (WES) to screen candidate pathogenic mutations. Here, we identified a heterozygous missense mutation in transcription factor-like 5 (TCFL5) (NM_006602.4: c.1207G > A: p.E403K) from two infertile brothers born into a non-consanguineous family. TCFL5 was previously linked to male infertility since Tcfl5+/− male mice manifested infertile due to OAT, while Tcfl5−/− mice could not be generated. Sperm morphological analysis of these brothers exhibited a similar OAT phenotype to Tcfl5+/− mice. In vitro functional analysis performed to explore the pathogenicity of TCFL5 mutation. Regardless of no significant effect on the expression of mutant TCFL5 detected by western blotting and immunofluorescence, dual-luciferase reporter assay revealed a serious impact on its transcriptional regulatory function. Many crucial genes involved in spermatogenesis, such as DMRT1, DAZL, SYCE1, SPACA1, CNTROB, IFT88, HOOK1 and SPATA6, occurred transcriptional abnormalities after TCFL5 mutated. Our results showed that TCFL5 mutation disrupted the normal transcription of spermatogenesis genes, finally resulting in male infertility raised by OAT. Our work firstly linked TCFL5 mutation to male infertility in human, which provides a new perspective on the genetic underpinnings of OAT and a theoretical basis for clinic genetic counseling and treatment strategies selection.