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Published on: December 28, 2021
CEP131 Deficiency Leads to Multiple Morphological Abnormalities of the Sperm Flagellum-Associated Male Infertility
Xueling Chen1, Zhuyu Li2, Wensheng Liu3,4,5
1Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
Background:
Multiple morphological abnormalities of the sperm flagellum (MMAF) is a phenotypically severe but genetically heterogeneous subtype of asthenoteratozoospermia. The genetic etiology of MMAF patients is still largely unknown.
Objectives:
To identify novel genetic factors contributing to MMAF-related male infertility and evaluate the therapeutic efficacy of intracytoplasmic sperm injection in affected patients.
Materials And Methods:
A cohort of 124 infertile males with typical MMAF were recruited. Novel pathogenic variants were identified through whole-exome sequencing and Sanger sequencing. Bioinformatics analysis revealed the effects of these variants. Sperm morphology and ultrastructural defects were observed using Papanicolaou staining and transmission electron microscopy. The expression and localization of relevant proteins were analyzed by immunofluorescence. CEP131 interaction proteins were identified via co-immunoprecipitation. The impact of pathogenic variants on fertilization and embryonic development was evaluated by intracytoplasmic sperm injection.
Results:
We identified bi-allelic CEP131 mutations in four patients with MMAF for the first time. These mutations are highly deleterious and rare in the human population. These mutations affect the expression of centrosome-related proteins CEP131, CEP290, and PCM1, and lead to centrosomal malformations. CEP131 interacts with CEP290 to regulate the formation of the sperm flagellum. Unfortunately, two patients were treated with ICSI but none of them obtained transferable blastocysts due to embryonic development arrest.
Conclusion:
This study provides the first evidence that CEP131 mutations cause MMAF and male infertility due to impairing sperm flagellar formation by interacting with CEP290. ICSI treatment showed a poor prognosis in our cases due to embryonic development arrest.
Insights
CEP131 gene mutations cause multiple morphological abnormalities of the sperm flagellum (MMAF), leading to male infertility. Intracytoplasmic sperm injection (ICSI) showed poor outcomes due to embryonic arrest in MMAF patients with these mutations.
Area of Science:
- Genetics
- Reproductive Biology
- Cell Biology
Background:
- Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe subtype of asthenoteratozoospermia with largely unknown genetic causes.
- Identifying the genetic basis of MMAF is crucial for understanding male infertility.
Purpose of the Study:
- To discover novel genetic factors responsible for MMAF.
- To assess the effectiveness of intracytoplasmic sperm injection (ICSI) for male infertility caused by MMAF.
Main Methods:
- Whole-exome and Sanger sequencing were used to identify genetic variants in 124 infertile males with MMAF.
- Sperm morphology, ultrastructure, and protein localization (CEP131, CEP290, PCM1) were analyzed.
- Co-immunoprecipitation identified CEP131 interacting proteins; ICSI outcomes were evaluated.
Main Results:
- Bi-allelic mutations in the CEP131 gene were identified in four MMAF patients, representing a novel genetic cause.
- These CEP131 mutations led to centrosomal malformations and impaired sperm flagellar formation.
- Two patients undergoing ICSI experienced embryonic development arrest, resulting in no transferable blastocysts.
Conclusions:
- CEP131 mutations are a newly identified cause of MMAF and male infertility by disrupting sperm flagellar development through interaction with CEP290.
- ICSI treatment for male infertility due to CEP131 mutations has a poor prognosis, with high rates of embryonic arrest.
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