Absence of murine CFAP61 causes male infertility due to multiple morphological abnormalities of the flagella

Huang, Tao; Yin, Yingying; Liu, Chao; Li, Mengjing; Yu, Xiaochen; Wang, Xiuge; Zhang, Haobo; Muhammad, Tahir; Gao, Fei; Li, Wei; Chen, Zi‐Jiang; Liu, Hongbin; Ma, Jinlong

doi:10.1016/j.scib.2020.01.023

Cited by 18 publications

(20 citation statements)

References 39 publications

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“…Almostall Cfap61 −/− spermatozoa were abnormal and showed short, bent, curled, thick or missing flagella (Figure 5-figure supplement 1). Similar phenotypes were reported in a contemporaneous study of another Cfap61 knockout mouse(Huang et al, 2020). The acrosome morphology of Cfap61 −/− sperm was normal, while the formation of the tail was clearly disordered (Figure 5B-F).…”

Section: Resultssupporting

confidence: 82%

CFAP61 is required for sperm flagellum formation and male fertility in human and mouse

Liu

Zhang

Kherraf

et al. 2021

Preprint

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Defects in the structure or motility of cilia and flagella may lead to severe diseases such as primary ciliary dyskinesia (PCD), a multisystemic disorder with heterogeneous manifestations affecting primarily respiratory and reproductive functions. We report that CFAP61 is a conserved component of the Calmodulin and radial Spoke associated Complex (CSC) of cilia. We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype. We generated Cfap61 knockout mice that recapitulate the infertility phenotype of the human CFAP61 mutation, but without other symptoms usually observed in PCD. We find that CFAP61 interacts with the CSC, radial spoke stalk and RS head. During early stages of Cfap61-/- spermatid development, the assembly of RS components is impaired. With the progress of spermiogenesis, the axoneme in Cfap61-/- cells becomes unstable and scatters, and the distribution of intraflagellar transport proteins is disrupted.

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Section: Resultssupporting

confidence: 82%

CFAP61 is required for sperm flagellum formation and male fertility in human and mouse

Liu

Zhang

Kherraf

et al. 2021

Preprint

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“…Since disruption of Cfap61 in mice was associated with the abnormalities of flagellum components (Huang et al, 2020), we thus investigated the ultrastructure of spermatozoa from the patients (P1-P6, P8, and P9) by TEM. In contrast to the typical "9 + 2" axoneme arrangement in the spermatozoa from a fertile control, most of the flagellar cross-sections from spermatozoa of patients exhibited severely disorganized axoneme structure, along with the missings of MTDs, dynein arms, RSs, and/or CP (Figure 2A).…”

Section: Homozygous Variants In Cfap61 Were Found In Patientsmentioning

confidence: 99%

“…Biallelic mutations in CFAP91 and CFAP251 have been reported in MMAF-affected individuals (Auguste et al, 2018;Kherraf et al, 2018;Li et al, 2019;Martinez et al, 2020). Moreover, Cfap61 knockout mice displayed multiple morphological and ultrastructural abnormalities, severely reduced sperm count and motility, and male infertility (Huang et al, 2020). Nonetheless, whether CFAP61 variants are also associated with MMAF in humans and the clinical manifestations of the CFAP61 genetic anomalies have not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility

Zeb

Ali

et al. 2022

Front. Cell Dev. Biol.

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Multiple morphological abnormalities of the flagella (MMAF) can lead to male infertility due to impaired sperm motility and morphology. Calmodulin- and spoke-associated complex (CSC) are known for their roles in radial spoke (RS) assembly and ciliary motility in Chlamydomonas, while the role of cilia- and flagella-associated protein 61 (CFAP61), a mammalian ortholog of the CSC subunits, in humans is yet unknown. Here, we recruited three unrelated Pakistani families comprising of 11 infertile male patients diagnosed with MMAF. CFAP61 variants, c.451_452del (p.I151Nfs*4) in family 1 and c.847C > T (p.R283*) in family 2 and 3, were identified recessively co-segregating with the MMAF phenotype. Transmission electron microscopy analyses revealed severe disorganized axonemal ultrastructures, and missings of central pair, RSs, and inner dynein arms were also observed and confirmed by immunofluorescence staining in spermatozoa from patients. CFAP61 and CFAP251 signals were absent from sperm tails of the patients, which suggested the loss of functional CSC in sperm flagella. Altogether, our findings report that homozygous variants in CFAP61 are associated with MMAF and male infertility, demonstrating the essential role of this gene in normal sperm flagellum structure in humans.

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“…The cilia and flagella associated protein (CFAP) family, such as CFAP58, CFAP61, CFAP69, CFAP65, CFAP43, CFAP44, CFAP70, and CFAP251, is associated with flagellum biogenesis and morphogenesis (Tang et al, 2017;Dong et al, 2018;Beurois et al, 2019;He et al, 2020;Huang et al, 2020;Li et al, 2020). Previous studies have indicated that the functional role of CFAP53 (also named the coiledcoil domain containing protein CCDC11) is involved in the biogenesis and motility of motile cilia (Perles et al, 2012;Narasimhan et al, 2015;Noël et al, 2016;Silva et al, 2016), and CFAP53 is localized not only to the base of the nodal cilia, but also along the axoneme of the tracheal cilia (Ide et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Essential Role of CFAP53 in Sperm Flagellum Biogenesis

Liu

et al. 2021

Front. Cell Dev. Biol.

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The sperm flagellum is essential for male fertility. Despite vigorous research progress toward understanding the pathogenesis of flagellum-related diseases, much remains unknown about the mechanisms underlying the flagellum biogenesis itself. Here, we show that the cilia and flagella associated protein 53 (Cfap53) gene is predominantly expressed in testes, and it is essential for sperm flagellum biogenesis. The knockout of this gene resulted in complete infertility in male mice but not in the females. CFAP53 localized to the manchette and sperm tail during spermiogenesis, the knockout of this gene impaired flagellum biogenesis. Furthermore, we identified two manchette and sperm tail-associated proteins that interacted with CFAP53 during spermiogenesis. Together, our results suggest that CFAP53 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with multiple morphological abnormalities of the flagella (MMAF).

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Absence of murine CFAP61 causes male infertility due to multiple morphological abnormalities of the flagella

Cited by 18 publications

References 39 publications

CFAP61 is required for sperm flagellum formation and male fertility in human and mouse

CFAP61 is required for sperm flagellum formation and male fertility in human and mouse

Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility

Essential Role of CFAP53 in Sperm Flagellum Biogenesis

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