ArticleHuman genomics2025
Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice.
Article in Human genomics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Flagellogenesis in mammalian sperm is essential for sperm motility and successful egg fertilization. Multiple morphological abnormalities of the sperm flagella (MMAF) represent a condition characterized by various structural defects in the flagellum. While CFAP57 has been identified as a factor in the pathogenic mechanisms of MMAF, the precise molecular regulation underlying this process remains unclear. Here, we report novel biallelic mutations in the CFAP57 gene identified in two infertile males from two unrelated families. The first patient carried a homozygous nonsense mutation in CFAP57 [NM_001195831.2: c.3250 C > T (p.R1084X)], while the second was compound heterozygous for two missense mutations c.1340T > C (p.V447A) and c.1856G > A (p.R619H). CRISPR-Cas9-generated CFAP57 mutant mice recapitulated human MMAF phenotypes, exhibiting structural flagellar defects and complete infertility. Using immunoprecipitation-mass spectrometry (IP-MS), we identified MYH10, a non-muscle myosin II isoform, as an interaction partner of CFAP57. Immunofluorescence analysis confirmed that both MYH10 and CFAP57 localize to the sperm flagella. We further examined the precise localization of MYH10 at the ultrastructural level using immunoelectron microscopy. Gold particles conjugated to the MYH10 antibody were predominantly detected in the sperm flagella. In sperm with CFAP57 mutations, MYH10 was mislocalized to the mid-piece region while being notably absent from the principal and end pieces. This mislocalization affected the expression of IFT88, a key component of the intraflagellar transport (IFT) system that plays a critical role in mammalian flagellar assembly. Fortunately, ICSI can overcome CFAP57-associated male infertility. Together, our findings establish CFAP57 as an important mediator of sperm flagellogenesis that orchestrates MYH10 and IFT88 positioning and intraflagellar transport dynamics to maintain flagellar integrity, providing molecular insights into MMAF-associated male infertility.
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