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

Abstract

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.

LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility

“…However, there are other RS components in which mutations only cause male infertility in mice and human. For example, WES of infertile males without PCD symptoms identified mutations in CFAP251 (Auguste et al, 2018;Kherraf et al, 2018) and CFAP61 (Liu et al, 2021;Ma et al, 2021). RSPH6 (Abbasi et al, 2018), CFAP251 (Kherraf et al, 2018), or CFAP61 deficiency also rendered male mice infertile but without gross abnormalities.…”

“…In Chlamydomonas reinhardtii, RS mutations paralyze the flagellar movement (Witman et al, 1978) and the axoneme lacking RS system shows reduced velocity of microtubule sliding by dyneins (Smith & Sale, 1992). In human and mouse, mutations in RS components or their absence cause primary ciliary dyskinesia (PCD) and/or male infertility due to the defective ciliary and flagellar beating (Abbasi et al, 2018;Liu et al, 2021;Sironen et al, 2020). These studies highlight the physiological importance of RS in regulating ciliary and flagellar movement.…”

“…~80% of male infertile patients manifest sperm motility defects (Curi et al, 2003) as infertile male with abnormal sperm morphology and/or reduced sperm count often accompany low motility (Cavarocchi et al, 2022;Toure et al, 2021). Recent whole exome sequencing studies identified genetic defects in RS components from idiopathic ASZ patients (Liu et al, 2021;Martinez et al, 2020;Shen et al, 2021). Mutant analyses using model organisms further elucidated the function of RS components in the flagellar movement and the pathogenic mechanisms (Liu et al, 2021;Martinez et al, 2020).…”

“…Recent whole exome sequencing studies identified genetic defects in RS components from idiopathic ASZ patients (Liu et al, 2021;Martinez et al, 2020;Shen et al, 2021). Mutant analyses using model organisms further elucidated the function of RS components in the flagellar movement and the pathogenic mechanisms (Liu et al, 2021;Martinez et al, 2020). Thus, WES combined with functional and structural analyses of mutants, especially in a mouse model, would be a powerful and direct approach to understand mammalian specific RS3 roles including sperm motility regulation and genetic etiologies causing male infertility.…”

Gonadotropin induction of spermiation in Senegalese sole: Effect of temperature and stripping time

“…These data therefore suggest that full maturation of Spz in the ED of the testis possibly occurs at 48 h post rLh induction. This conclusion is supported by the expression of other genes potentially involved in sperm motility, such as cfap46, cfap54 and cfap61 (Linck et al, 2016;McKenzie et al, 2020;Huang et al, 2020;Liu et al, 2021), and sperm fertilization competence, such as spag6 and spa17 (Liu et al, 2019;Instaqui et al, 2017), which were also upregulated in the testis at 48 h after rLh injection.…”