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Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice
Ao Ma1, Jianteng Zhou1, Haider Ali1
1Division of Reproduction and Genetics, First Affiliated Hospital of University of Science and Technology of China (USTC), Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China.
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.
Insights
Pathogenic mutations in cilia and flagella associated protein 57 (CFAP57) cause multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility. CFAP57 is crucial for inner dynein arm assembly in sperm flagella, impacting male fertility.
Area of Science:
- Human genetics
- Reproductive biology
- Molecular cell biology
Background:
- Multiple morphological abnormalities of the sperm flagella (MMAF) represent a severe form of asthenozoospermia, characterized by impaired sperm axoneme structure.
- Dynein arms are essential components of the sperm flagellar axoneme, critical for motility.
Purpose of the Study:
- To identify the genetic cause of MMAF in consanguineous Pakistani families.
- To investigate the role of CFAP57 in sperm flagellar structure and male fertility.
Main Methods:
- Whole-exome sequencing and Sanger sequencing were used to identify mutations in affected individuals from three families.
- A mouse model was generated to mimic a identified CFAP57 mutation.
- Spermatozoa from affected individuals and the mouse model were analyzed to assess CFAP57 protein expression and flagellar structure.
Main Results:
- Two novel loss-of-function mutations in CFAP57 were identified, segregating with male infertility in affected families.
- CFAP57 deficiency led to the loss of the long transcript-encoded protein and disrupted inner dynein arm assembly in sperm flagella.
- The mouse model recapitulated the MMAF phenotype observed in human patients.
Conclusions:
- Pathogenic mutations in CFAP57 are a cause of MMAF and male infertility.
- The long transcript-encoded CFAP57 plays a critical role in the assembly of inner dynein arms in sperm flagella.
- CFAP57 is essential for maintaining male fertility.
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