ArticleAmerican journal of human genetics2020
Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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67 citing papers in PubMed, 1 synthesis or guideline pooled it, 114 citations in OpenAlex.
- The impact of mitochondrial impairments on sperm function and male fertility: a systematic review.Reproductive biology and endocrinology : RB&E · 2024Pooled it
- CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI.Journal of assisted reproduction and genetics · 2026Article
- Rare missense variants identified by whole-genome sequencing in men with oligoasthenoteratozoospermia: An experimental study.International journal of reproductive biomedicine · 2026Article
- Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas.eLife · 2026Article
- Biallelic loss-of-function variants in DNAH12 cause inner dynein arm defects and sperm head abnormalities leading to male infertility.Journal of assisted reproduction and genetics · 2026Article
- Regulation of mitochondrial function during spermatogenesis and sperm maturation.Cellular & molecular biology letters · 2026Review
- Proteostasis, Assisted Reproductive Technologies, and Neurodevelopmental Differences: An Integrative Perspective.Proteomes · 2026Review
- Role of SPAG6 in regulating physiological functions and tumorigenesis (Review).International journal of oncology · 2026Review
- SIRT1 haploinsufficiency recapitulates age-associated subfertility through sperm α-tubulin hyperacetylation.Biology direct · 2026Article
- Novel biallelic DNHD1 variants associated with male infertility with severe MMAF phenotype.Asian journal of andrology · 2026Article
- Mapping the Non-Canonical Splicing Variants: Decrypting the Hidden Genetic Architecture of Idiopathic Male Infertility.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Heat shock proteins in male infertility: recent advances and clinical implications.Frontiers in cell and developmental biology · 2026Review
- A Novel Homozygous Mutation inHuman mutation · 2026Article
- Pathogenic Variants in PET Complex Encoding GenesHuman mutation · 2026Article
- Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice.Human genomics · 2025Article
- Male infertility.Systems biology in reproductive medicine · 2025Review
- CFAP300 loss-of-function variant causes primary ciliary dyskinesia and male infertility via disrupting sperm flagellar assembly and acrosome formation.Asian journal of andrology · 2025Article
- The TEX44-CPT1B axis regulates mitochondrial sheath assembly and fatty acid oxidation in sperm.Nature communications · 2025Article
- How exome sequencing improves the diagnostics and management of men with non-syndromic infertility.Andrology · 2025Review
- Human asthenozoospermia: Update on genetic causes, patient management, and clinical strategies.Andrology · 2025Review
7 more citing papers are in PubMed but not listed here.
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Authors and funding
32 authors at 7 institutions in 1 country.
Xiaojin HeReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Chunyu LiuObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Xiaoyu YangState Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Mingrong LvReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Xiaoqing NiReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Qiang LiReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Huiru ChengReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei 230032, China; Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China.
Wangjie LiuObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Shixiong TianObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
Huan WuReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Yang GaoReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Chenyu YangCenter of Cryo-Electron Microscopy, Zhejiang University, Hangzhou 310058, China.
Qing TanReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Jiangshan CongObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
Dongdong TangReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Jingjing ZhangReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Bing SongReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Yading ZhongDepartment of Radiology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Hang LiReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Weiwei ZhiReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Xiaohong MaoReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Feifei FuReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Lei GeReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Provincial Human Sperm Bank, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Qunshan ShenReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei 230032, China; Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China.
Manyu ZhangReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Hefei 230032, China; Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei 230032, China.
Hexige SaiyinObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China.
Li JinObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China.
Yuping XuReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Ping ZhouReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Zhaolian WeiReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China.
Feng ZhangObstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai 200011, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China; State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Electronic address: zhangfeng@fudan.edu.cn.
Yunxia CaoReproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract (Anhui Medical University), Hefei 230032, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, Hefei 230032, China. Electronic address: caoyunxia6@126.com.
First Affiliated Hospital of Anhui Medical University · CNAnhui Medical University · CNMinistry of Education of the People's Republic of China · CNFudan University · CNShanghai Institute of Planned Parenthood Research · CNNanjing Medical University · CNZhejiang University · CN
Funding
No grant is acknowledged in the PubMed record.
Abstract
Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.
Indexed as
Abnormalities, MultipleAllelesAnimalsAsthenozoospermiaAxonemeCell Cycle ProteinsCRISPR-Cas SystemsExome SequencingHomozygoteHumansInfertility, MaleIntercellular Signaling Peptides and ProteinsLoss of Function MutationLoss of HeterozygosityMaleMiceCell Cycle ProteinsIntercellular Signaling Peptides and ProteinsMicrotubule ProteinsSPAG6 protein, humanSPEF2 protein, humanasthenoteratozoospermiaCFAP58flagellummitochondrial sheathMMAF
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