Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice
Multiple morphological abnormalities of the sperm flagella (MMAF) are the most severe form of asthenozoospermia due to impaired axoneme structure in sperm flagella. Dynein arms are necessary components of the sperm flagellar axoneme. In this study, we recruited 3 unrelated consanguineous Pakistani f...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-02-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.166869 |
| _version_ | 1797634336260882432 |
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| author | Ao Ma Jianteng Zhou Haider Ali Tanveer Abbas Imtiaz Ali Zubair Muhammad Sobia Dil Jing Chen Xiongheng Huang Hui Ma Daren Zhao Beibei Zhang Yuanwei Zhang Wasim Shah Basit Shah Ghulam Murtaza Furhan Iqbal Muzammil Ahmad Khan Asad Khan Qing Li Bo Xu Limin Wu Huan Zhang Qinghua Shi |
| author_facet | Ao Ma Jianteng Zhou Haider Ali Tanveer Abbas Imtiaz Ali Zubair Muhammad Sobia Dil Jing Chen Xiongheng Huang Hui Ma Daren Zhao Beibei Zhang Yuanwei Zhang Wasim Shah Basit Shah Ghulam Murtaza Furhan Iqbal Muzammil Ahmad Khan Asad Khan Qing Li Bo Xu Limin Wu Huan Zhang Qinghua Shi |
| author_sort | Ao Ma |
| collection | DOAJ |
| description | Multiple morphological abnormalities of the sperm flagella (MMAF) are the most severe form of asthenozoospermia due to impaired axoneme structure in sperm flagella. Dynein arms are necessary components of the sperm flagellar axoneme. In this study, we recruited 3 unrelated consanguineous Pakistani families with multiple MMAF-affected individuals, who had no overt ciliary symptoms. Whole-exome sequencing and Sanger sequencing identified 2 cilia and flagella associated protein 57 (CFAP57) loss-of-function mutations (c.2872C>T, p. R958*; and c.2737C>T, p. R913*) recessively segregating with male infertility. A mouse model mimicking the mutation (c.2872C>T) was generated and recapitulated the typical MMAF phenotype of CFAP57-mutated individuals. Both CFAP57 mutations caused loss of the long transcript-encoded CFAP57 protein in spermatozoa from MMAF-affected individuals or from the Cfap57-mutant mouse model while the short transcript was not affected. Subsequent examinations of the spermatozoa from Cfap57-mutant mice revealed that CFAP57 deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that single-headed IDAs were more likely to be affected. Thus, our study identified 2 pathogenic mutations in CFAP57 in MMAF-affected individuals and reported a conserved and pivotal role for the long transcript-encoded CFAP57 in IDAs’ assembly and male fertility. |
| first_indexed | 2024-03-11T12:07:12Z |
| format | Article |
| id | doaj.art-f82907d9693b44eba88d929c6bce2d9b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:12Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-f82907d9693b44eba88d929c6bce2d9b2023-11-07T16:25:10ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-02-0183Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and miceAo MaJianteng ZhouHaider AliTanveer AbbasImtiaz AliZubair MuhammadSobia DilJing ChenXiongheng HuangHui MaDaren ZhaoBeibei ZhangYuanwei ZhangWasim ShahBasit ShahGhulam MurtazaFurhan IqbalMuzammil Ahmad KhanAsad KhanQing LiBo XuLimin WuHuan ZhangQinghua ShiMultiple morphological abnormalities of the sperm flagella (MMAF) are the most severe form of asthenozoospermia due to impaired axoneme structure in sperm flagella. Dynein arms are necessary components of the sperm flagellar axoneme. In this study, we recruited 3 unrelated consanguineous Pakistani families with multiple MMAF-affected individuals, who had no overt ciliary symptoms. Whole-exome sequencing and Sanger sequencing identified 2 cilia and flagella associated protein 57 (CFAP57) loss-of-function mutations (c.2872C>T, p. R958*; and c.2737C>T, p. R913*) recessively segregating with male infertility. A mouse model mimicking the mutation (c.2872C>T) was generated and recapitulated the typical MMAF phenotype of CFAP57-mutated individuals. Both CFAP57 mutations caused loss of the long transcript-encoded CFAP57 protein in spermatozoa from MMAF-affected individuals or from the Cfap57-mutant mouse model while the short transcript was not affected. Subsequent examinations of the spermatozoa from Cfap57-mutant mice revealed that CFAP57 deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that single-headed IDAs were more likely to be affected. Thus, our study identified 2 pathogenic mutations in CFAP57 in MMAF-affected individuals and reported a conserved and pivotal role for the long transcript-encoded CFAP57 in IDAs’ assembly and male fertility.https://doi.org/10.1172/jci.insight.166869Reproductive biology |
| spellingShingle | Ao Ma Jianteng Zhou Haider Ali Tanveer Abbas Imtiaz Ali Zubair Muhammad Sobia Dil Jing Chen Xiongheng Huang Hui Ma Daren Zhao Beibei Zhang Yuanwei Zhang Wasim Shah Basit Shah Ghulam Murtaza Furhan Iqbal Muzammil Ahmad Khan Asad Khan Qing Li Bo Xu Limin Wu Huan Zhang Qinghua Shi Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice JCI Insight Reproductive biology |
| title | Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice |
| title_full | Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice |
| title_fullStr | Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice |
| title_full_unstemmed | Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice |
| title_short | Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice |
| title_sort | loss of function mutations in cfap57 cause multiple morphological abnormalities of the flagella in humans and mice |
| topic | Reproductive biology |
| url | https://doi.org/10.1172/jci.insight.166869 |
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