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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...

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Autores principales: Ma, Ao, Zhou, Jianteng, Ali, Haider, Abbas, Tanveer, Ali, Imtiaz, Muhammad, Zubair, Dil, Sobia, Chen, Jing, Huang, Xiongheng, Ma, Hui, Zhao, Daren, Zhang, Beibei, Zhang, Yuanwei, Shah, Wasim, Shah, Basit, Murtaza, Ghulam, Iqbal, Furhan, Khan, Muzammil Ahmad, Khan, Asad, Li, Qing, Xu, Bo, Wu, Limin, Zhang, Huan, Shi, Qinghua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977434/
https://www.ncbi.nlm.nih.gov/pubmed/36752199
http://dx.doi.org/10.1172/jci.insight.166869
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author Ma, Ao
Zhou, Jianteng
Ali, Haider
Abbas, Tanveer
Ali, Imtiaz
Muhammad, Zubair
Dil, Sobia
Chen, Jing
Huang, Xiongheng
Ma, Hui
Zhao, Daren
Zhang, Beibei
Zhang, Yuanwei
Shah, Wasim
Shah, Basit
Murtaza, Ghulam
Iqbal, Furhan
Khan, Muzammil Ahmad
Khan, Asad
Li, Qing
Xu, Bo
Wu, Limin
Zhang, Huan
Shi, Qinghua
author_facet Ma, Ao
Zhou, Jianteng
Ali, Haider
Abbas, Tanveer
Ali, Imtiaz
Muhammad, Zubair
Dil, Sobia
Chen, Jing
Huang, Xiongheng
Ma, Hui
Zhao, Daren
Zhang, Beibei
Zhang, Yuanwei
Shah, Wasim
Shah, Basit
Murtaza, Ghulam
Iqbal, Furhan
Khan, Muzammil Ahmad
Khan, Asad
Li, Qing
Xu, Bo
Wu, Limin
Zhang, Huan
Shi, Qinghua
author_sort Ma, Ao
collection PubMed
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.
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spelling pubmed-99774342023-03-02 Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice Ma, Ao Zhou, Jianteng Ali, Haider Abbas, Tanveer Ali, Imtiaz Muhammad, Zubair Dil, Sobia Chen, Jing Huang, Xiongheng Ma, Hui Zhao, Daren Zhang, Beibei Zhang, Yuanwei Shah, Wasim Shah, Basit Murtaza, Ghulam Iqbal, Furhan Khan, Muzammil Ahmad Khan, Asad Li, Qing Xu, Bo Wu, Limin Zhang, Huan Shi, Qinghua JCI Insight Research Article 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. American Society for Clinical Investigation 2023-02-08 /pmc/articles/PMC9977434/ /pubmed/36752199 http://dx.doi.org/10.1172/jci.insight.166869 Text en © 2023 Ma et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Ma, Ao
Zhou, Jianteng
Ali, Haider
Abbas, Tanveer
Ali, Imtiaz
Muhammad, Zubair
Dil, Sobia
Chen, Jing
Huang, Xiongheng
Ma, Hui
Zhao, Daren
Zhang, Beibei
Zhang, Yuanwei
Shah, Wasim
Shah, Basit
Murtaza, Ghulam
Iqbal, Furhan
Khan, Muzammil Ahmad
Khan, Asad
Li, Qing
Xu, Bo
Wu, Limin
Zhang, Huan
Shi, Qinghua
Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice
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 Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9977434/
https://www.ncbi.nlm.nih.gov/pubmed/36752199
http://dx.doi.org/10.1172/jci.insight.166869
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