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Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice
Ao Ma, … , Huan Zhang, Qinghua Shi
Ao Ma, … , Huan Zhang, Qinghua Shi
Published February 8, 2023
Citation Information: JCI Insight. 2023;8(3):e166869. https://doi.org/10.1172/jci.insight.166869.
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Research Article Reproductive biology

Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice

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Abstract

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.

Authors

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

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Figure 1

Affected individuals from 3 unrelated consanguineous Pakistani families.

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Affected individuals from 3 unrelated consanguineous Pakistani families....
(A) Pedigrees of family 1 with 4 infertile cases, P1 (IV:5), P2 (IV:6), and P3 (IV:7); family 2 with 2 infertile cases, P4 (II:2) and P5 (II:4); and family 3 with 2 infertile cases, P6 (IV:3) and P7 (IV:9). Arrows point to the individuals for which WES was performed. Slashes denote deceased family members, and double horizontal lines represent consanguineous marriages. (B) Representative SEM micrographs showing sperm morphological abnormalities observed in P2, including absent, short, coiled, bent, and irregular-caliber flagella. A representative spermatozoon with normal morphology from the fertile control was shown. Scale bars represent 5 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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