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Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and

Yongjie Chen1, Lin Li2, Ranran Meng3,4

  • 1Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China. chenyongjie@ccmu.edu.cn.

Human Genomics
|December 30, 2025
PubMed

Insights

Novel mutations in the CFAP57 gene cause male infertility by disrupting sperm flagella formation. This study identifies MYH10 and IFT88 as key players in CFAP57-mediated sperm development, offering insights into Multiple Morphological Abnormalities of the Sperm Flagella.

Area of Science:

  • Reproductive Biology
  • Genetics
  • Cell Biology

Background:

  • Sperm flagella are crucial for motility and fertilization.
  • Multiple Morphological Abnormalities of the Sperm Flagella (MMAF) is a condition causing structural flagellar defects and infertility.
  • CFAP57's role in MMAF pathogenesis is known, but its precise molecular regulation is unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying CFAP57-associated male infertility.
  • To identify novel mutations in CFAP57 causing MMAF.
  • To elucidate the interaction partners and functional role of CFAP57 in sperm flagellogenesis.

Main Methods:

  • Genetic analysis of infertile males to identify CFAP57 mutations.
  • CRISPR-Cas9 gene editing in mice to model human MMAF phenotypes.
  • Immunoprecipitation-mass spectrometry (IP-MS) to identify CFAP57 interaction partners.
  • Immunofluorescence and immunoelectron microscopy to analyze protein localization and ultrastructure.

Main Results:

  • Identified novel biallelic CFAP57 mutations (nonsense and missense) in two infertile families.
  • CFAP57 mutant mice exhibited flagellar defects and infertility, mirroring human MMAF.
  • MYH10 was identified as a CFAP57 interaction partner, crucial for flagellar structure.
  • CFAP57 mutations led to MYH10 mislocalization, affecting IFT88 expression and intraflagellar transport.
  • Intracytoplasmic sperm injection (ICSI) can overcome this infertility.

Conclusions:

  • CFAP57 is essential for sperm flagellogenesis, regulating MYH10 and IFT88 positioning.
  • Disruptions in CFAP57-mediated pathways lead to MMAF and male infertility.
  • Findings provide molecular insights into CFAP57-associated infertility and potential therapeutic strategies.
Keywords:
CFAP57ICSIIFT88MMAFMYH10Male infertility

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