Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility
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 cili...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.803818/full |
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| author | Ao Ma Aurang Zeb Imtiaz Ali Daren Zhao Asad Khan Beibei Zhang Jianteng Zhou Ranjha Khan Huan Zhang Yuanwei Zhang Ihsan Khan Wasim Shah Haider Ali Abdul Rafay Javed Hui Ma Qinghua Shi |
| author_facet | Ao Ma Aurang Zeb Imtiaz Ali Daren Zhao Asad Khan Beibei Zhang Jianteng Zhou Ranjha Khan Huan Zhang Yuanwei Zhang Ihsan Khan Wasim Shah Haider Ali Abdul Rafay Javed Hui Ma Qinghua Shi |
| author_sort | Ao Ma |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T19:10:47Z |
| format | Article |
| id | doaj.art-3051006f8bdd46a1ad8bc5074bbd8bf2 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T19:10:47Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-3051006f8bdd46a1ad8bc5074bbd8bf22022-12-21T21:35:52ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-01-01910.3389/fcell.2021.803818803818Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male InfertilityAo MaAurang ZebImtiaz AliDaren ZhaoAsad KhanBeibei ZhangJianteng ZhouRanjha KhanHuan ZhangYuanwei ZhangIhsan KhanWasim ShahHaider AliAbdul Rafay JavedHui MaQinghua ShiMultiple 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.803818/fullmale infertilitymultiple morphological abnormalities of flagellacentral paircalmodulin- and spoke-associated complexCfap61 |
| spellingShingle | Ao Ma Aurang Zeb Imtiaz Ali Daren Zhao Asad Khan Beibei Zhang Jianteng Zhou Ranjha Khan Huan Zhang Yuanwei Zhang Ihsan Khan Wasim Shah Haider Ali Abdul Rafay Javed Hui Ma Qinghua Shi Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility Frontiers in Cell and Developmental Biology male infertility multiple morphological abnormalities of flagella central pair calmodulin- and spoke-associated complex Cfap61 |
| title | Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility |
| title_full | Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility |
| title_fullStr | Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility |
| title_full_unstemmed | Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility |
| title_short | Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility |
| title_sort | biallelic variants in cfap61 cause multiple morphological abnormalities of the flagella and male infertility |
| topic | male infertility multiple morphological abnormalities of flagella central pair calmodulin- and spoke-associated complex Cfap61 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.803818/full |
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