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

Liu, Siyu; Zhang, Jintao; Kherraf, Zine‐Eddine; Sun, Shihui; Zhang, Xin; Cazin, Caroline; Coutton, Charles; Zouari, Raoudha; Zhao, Shuqin; Hu, Fan; Mustapha, Sélima Fourati Ben; Arnoult, Christophe; Ray, Pierre F.; Liu, Mingxi

doi:10.1242/dev.199805

Cited by 36 publications

(26 citation statements)

References 67 publications

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“…About 35–60% of MMAF infertility cases are associated with a genetic etiology, and MMAF has been reported to be associated with a variety of genes in humans and in mice [ 9 ]. In previous studies, several gene-families were identified to be associated with flagella, including the AKAP family, DANI family, DNAH family, RSPH family, CCDC family, CFAP family, TTC family, and some single genes [ 1 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ]. In the AKAP family, AKAP3 and AKAP4 mutations were identified causing dysplasia of the fibrous sheath, presenting MMAF phenotypes and male infertility [ 12 , 14 , 15 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in CCDC39, CCDC40, and CCDC103 presented cilia axonemal disorganization, absent inner dynein arms, and male infertility [ 27 , 28 , 29 ]. Several CFAP family genes were associated with cilia and flagella abnormalities in human and mutant mouse models, including CFAP43, CFAP44, CFAP58, CFAP61, CFAP65, CFAP69, CFAP70, and CFAP251, are associated with flagellum biogenesis and morphogenesis, when mutant, caused MMAF and male infertility [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. Furthermore, whole-exome sequencing (WES) identified FSIP2, DZIP1, and QRICH2 were associated with MMAF, and defected the axoneme [ 40 , 41 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Genetic origin accounts for 35–60% of these MMAF cases. Several gene-families are identified as associated with flagella, including the AKAP family, DANI family, DNAH family, RSPH family, CCDC family, CFAP family, TTC family, and some single genes [ 1 , 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

Section: Introductionmentioning

confidence: 99%

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LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse

Yin

et al. 2022

IJMS

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The sperm flagellum is essential for male fertility. Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. MMAF phenotypes are understood to result from pathogenic variants of genes from multiple families including AKAP, DANI, DNAH, RSPH, CCDC, CFAP, TTC, and LRRC, among others. The Leucine-rich repeat protein (LRRC) family includes two members reported to cause MMAF phenotypes: Lrrc6 and Lrrc50. Despite vigorous research towards understanding the pathogenesis of MMAF-related diseases, many genes remain unknown underlying the flagellum biogenesis. Here, we found that Leucine-rich repeat containing 46 (LRRC46) is specifically expressed in the testes of adult mice, and show that LRRC46 is essential for sperm flagellum biogenesis. Both scanning electron microscopy (SEM) and Papanicolaou staining (PS) presents that the knockout of Lrrc46 in mice resulted in typical MMAF phenotypes, including sperm with short, coiled, and irregular flagella. The male KO mice had reduced total sperm counts, impaired sperm motility, and were completely infertile. No reproductive phenotypes were detected in Lrrc46−/−female mice. Immunofluorescence (IF) assays showed that LRRC46 was present throughout the entire flagella of control sperm, albeit with evident concentration at the mid-piece. Transmission electron microscopy (TEM) demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. About the important part of the Materials and Methods, SEM and PS were used to observe the typical MMAF-related irregular flagella morphological phenotypes, TEM was used to further inspect the sperm flagellum defects in ultrastructure, and IF was chosen to confirm the location of protein. Our study suggests that LRRC46 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with MMAF that causes male infertility. Thus, our study provides insights for understanding developmental processes underlying sperm flagellum formation and contribute to further observe the pathogenic genes that cause male infertility.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse

Yin

et al. 2022

IJMS

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“…However, among the reported causative genes, few are directly related to FSs. FSIP2 , which encodes a FS-interacting protein, is involved in FS assembly, and FSIP2 defects have been reported to be related to MMAF ( Martinez et al, 2018 ; Liu Y. et al, 2019 ; Liu S. et al, 2021 ; Fang et al, 2021 ; Hou et al, 2022 ; Yuan et al, 2022 ; Zheng et al, 2022 ). In patients harboring FSIP2 mutations, the defects in sperm are not limited to abnormalities in the FS but also cause abnormalities in the microtubule skeleton.…”

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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“…Interestingly, in humans, mutations in genes orthologous to SPEF2A (SPEF2) and CFAP69 turned out to cause MMAF and very rarely PCD (until now, only mutations in SPEF2 were connected to PCD) [190][191][192][193][194][195]. Among other MMAF-causative genes [196,197] studied in Tetrahymena are, as mentioned before, CFAP43 and CFAP44 [127,[198][199][200][201][202], the CSC subunits CFAP61 [203,204] and CFAP251 [204,205], and CFAP206, which forms a part of the RS2 base [126,196].…”

Section: Ciliate: Tetrahymena and Parameciummentioning

confidence: 99%

PCD Genes—From Patients to Model Organisms and Back to Humans

Niziolek

Osinka

Samsel

et al. 2022

IJMS

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Primary ciliary dyskinesia (PCD) is a hereditary genetic disorder caused by the lack of motile cilia or the assembxly of dysfunctional ones. This rare human disease affects 1 out of 10,000–20,000 individuals and is caused by mutations in at least 50 genes. The past twenty years brought significant progress in the identification of PCD-causative genes and in our understanding of the connections between causative mutations and ciliary defects observed in affected individuals. These scientific advances have been achieved, among others, due to the extensive motile cilia-related research conducted using several model organisms, ranging from protists to mammals. These are unicellular organisms such as the green alga Chlamydomonas, the parasitic protist Trypanosoma, and free-living ciliates, Tetrahymena and Paramecium, the invertebrate Schmidtea, and vertebrates such as zebrafish, Xenopus, and mouse. Establishing such evolutionarily distant experimental models with different levels of cell or body complexity was possible because both basic motile cilia ultrastructure and protein composition are highly conserved throughout evolution. Here, we characterize model organisms commonly used to study PCD-related genes, highlight their pros and cons, and summarize experimental data collected using these models.

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

Cited by 36 publications

References 67 publications

LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse

LRRC46 Accumulates at the Midpiece of Sperm Flagella and Is Essential for Spermiogenesis and Male Fertility in Mouse

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

PCD Genes—From Patients to Model Organisms and Back to Humans

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