Biallelic<i>CFAP61</i>variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Hu, Tongyao; Meng, Lanlan; Tan, Chen; Luo, Chen; He, Wen‐Bin; Tu, Chaofeng; Zhang, Huan; Du, Juan; Nie, Hongchuan; Lu, Guangxiu; Lin, Ge; Tan, Yue‐Qiu

doi:10.1136/jmedgenet-2021-108249

Cited by 19 publications

(12 citation statements)

References 33 publications

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“…As the deletion of axonemal proteins frequently disrupts the structural integrity of the axoneme ( 6 , 11 , 26 ), TEM was next used to assess the ultrastructural characteristics of the flagella ( Figure 3 ). Midpiece sections from both a normal control donor and the two KIF9- deficient probands showed mitochondria forming an outer layer with a central axoneme surrounded by ODFs.…”

Section: Resultsmentioning

confidence: 99%

“…Sperm flagella consist of an evolutionarily conserved axoneme core, composed of nine outer microtubule doublets (DMTs) and a central pair (CP) of microtubules in a 9 + 2 structure. The flagella also include periaxonemal structures, including the mitochondrial sheath (MS) and fibrous sheath (FS) in the midpiece and principal piece regions, respectively, as well as outer dense fibers (ODFs) present in both the midpiece and proximal principal piece regions (6). To date, many singlegene variants have been shown to cause AZS and associated morphological defects by damaging the integrity of these flagellar structures (7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Identification of bi-allelic KIF9 loss-of-function variants contributing to asthenospermia and male infertility in two Chinese families

Meng

Gao

et al. 2023

Front. Endocrinol.

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IntroductionAsthenozoospermia (AZS) is a leading cause of male infertility, affecting an estimated 18% of infertile patients. Kinesin proteins function as molecular motors capable of moving along microtubules. The highly conserved kinesin family member 9 (KIF9) localizes to the central microtubule pair in the flagella of Chlamydomonas cells. The loss of KIF9 expression in mice has been linked to AZS phenotypes.MethodsVariant screening was performed by whole exome sequencing from 92 Chinese infertile patients with AZS. Western blot was used to was used for analyzing of candidate proteins expression. Patients’ sperm samples were stained with immunofluorescent to visualise proteins localization and were visualised by transmission electron microscopy (TEM) to determine axoneme structures. Co-immunoprecipitation assay was used to verify the binding proteins of KIF9. In vitro fertilization (IVF) was used to evaluate the efficiency of clinical treatment.ResultsBi-allelic KIF9 loss-of-function variants were identified in two unrelated Chinese males exhibiting atypical sperm motility phenotypes. Both of these men exhibited typical AZS and suffered from infertility together with the complete absence of KIF9 expression. In contrast to these KIF9-deficient patients, positive KIF9 staining was evident throughout the flagella of sperm from normal control individuals. KIF9 was able to interact with the microtubule central pair (CP) component hydrocephalus-inducing protein homolog (HYDIN) in human samples. And KIF9 was undetectable in spermatozoa harboring CP deletions. The morphologicy of KIF9-deficient spermatozoa appeared normal under gross examination and TEM. Like in mice, in vitro fertilization was sufficient to overcome the fertility issues for these two patientsDiscussionThese findings indicate that KIF9 associates with the central microtubules in human sperm and that it functions to specifically regulate flagellar swinging. Overall, these results offer greater insight into the biological functions of KIF9 in the assembly of the human flagella and its role in male fertility.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of bi-allelic KIF9 loss-of-function variants contributing to asthenospermia and male infertility in two Chinese families

Meng

Gao

et al. 2023

Front. Endocrinol.

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“…RS1 is adjacent to the base of the inner dynein arm, while RS2 and RS3are respectively attached to the front and back of the nexin–dynein regulatory complex (N-DRC) and the calmodulin- and spoke-associated complex (CSC) ( Zhu et al, 2017 ). Defects of several genes that encode CSC components have been reported to be related to MMAF, including CFAP61 ( Ma A. et al, 2021 ; Liu M. et al, 2021 ; Hu et al, 2022 ), CFAP91 ( Martinez et al, 2020 ), CFAP206 ( Shen et al, 2021 ) and CFAP251 ( Auguste et al, 2018 ; Kherraf et al, 2018 ; Li W. et al, 2019 ; Wang J. et al, 2021 ). Early in 2007, Dymek and Smith conducted immunoprecipitation experiments using anti-CaM antibodies and found that the CSC is comprised of three polypeptides, namely, CaM-IP2, CaM-IP3 and CaM-IP4, which are also termed as CFAP61, CFAP91 and CFAP251, respectively ( Dymek and Smith, 2007 ).…”

Section: Pathogenic Genes and Their Function Inspermatogenesismentioning

confidence: 99%

Clinical detection, diagnosis and treatment of morphological abnormalities of sperm flagella: A review of literature

Wang

Zheng

et al. 2022

Front. Genet.

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Sperm carries male genetic information, and flagella help move the sperm to reach oocytes. When the ultrastructure of the flagella is abnormal, the sperm is unable to reach the oocyte and achieve insemination. Multiple morphological abnormalities of sperm flagella (MMAF) is a relatively rare idiopathic condition that is mainly characterized by multiple defects in sperm flagella. In the last decade, with the development of high-throughput DNA sequencing approaches, many genes have been revealed to be related to MMAF. However, the differences in sperm phenotypes and reproductive outcomes in many cases are attributed to different pathogenic genes or different pathogenic mutations in the same gene. Here, we will review information about the various phenotypes resulting from different pathogenic genes, including sperm ultrastructure and encoding proteins with their location and functions as well as assisted reproductive technology (ART) outcomes. We will share our clinical detection and diagnosis experience to provide additional clinical views and broaden the understanding of this disease.

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“…Mutations in genes encoding CSC components also affect proper cilia/flagella functioning in vertebrates. In humans, mutations in genes encoding CFAP61 [ 22 , 23 , 24 ], CFAP91/AAT1/MAATS1/C3orf15 [ 19 ], or CFAP251/WDR66 [ 20 , 25 , 26 , 27 ] cause male infertility. This agrees with the gene expression studies in mice [ 23 ] and human tissues [ 28 , 29 ], showing that CFAP61 , CFAP91 , and CFAP251 are highly expressed in testis.…”

Section: Introductionmentioning

confidence: 99%

Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia

Joachimiak

Urbańska

Osinka

et al. 2022

Cells

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Motile cilia and eukaryotic flagella are specific cell protrusions that are conserved from protists to humans. They are supported by a skeleton composed of uniquely organized microtubules—nine peripheral doublets and two central singlets (9 × 2 + 2). Microtubules also serve as docking sites for periodically distributed multiprotein ciliary complexes. Radial spokes, the T-shaped ciliary complexes, repeat along the outer doublets as triplets and transduce the regulatory signals from the cilium center to the outer doublet-docked dynein arms. Using the genetic, proteomic, and microscopic approaches, we have shown that lack of Tetrahymena Cfap91 protein affects stable docking/positioning of the radial spoke RS3 and the base of RS2, and adjacent inner dynein arms, possibly due to the ability of Cfap91 to interact with a molecular ruler protein, Ccdc39. The localization studies confirmed that the level of RS3-specific proteins, Cfap61 and Cfap251, as well as RS2-associated Cfap206, are significantly diminished in Tetrahymena CFAP91-KO cells. Cilia of Tetrahymena cells with knocked-out CFAP91 beat in an uncoordinated manner and their beating frequency is dramatically reduced. Consequently, CFAP91-KO cells swam about a hundred times slower than wild-type cells. We concluded that Tetrahymena Cfap91 localizes at the base of radial spokes RS2 and RS3 and likely plays a role in the radial spoke(s) positioning and stability.

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BiallelicCFAP61variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia

Cited by 19 publications

References 33 publications

Identification of bi-allelic KIF9 loss-of-function variants contributing to asthenospermia and male infertility in two Chinese families

Identification of bi-allelic KIF9 loss-of-function variants contributing to asthenospermia and male infertility in two Chinese families

Clinical detection, diagnosis and treatment of morphological abnormalities of sperm flagella: A review of literature

Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia

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