Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella
Open accessAbstract
Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAF-associated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia- and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43- and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.
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Several proteins in spermatogenesis seem to carry two HHMCs: SSFA2, SPAG17, ADAM18 and WDR52, out of which ADAM18 and SPAG17 also carry AHMCs.
“we find that several proteins in spermatogenesis seem to carry two HHMCs: Sperm Specific Antigen 2 (SSFA2), Sperm Associated Antigen 17 (SPAG17), ADAM18172 and WDR52173, out of which ADAM18 and SPAG17 also carry AHMCs.”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [173]
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A catalog of single nucleotide changes distinguishing modern humans from archaic hominins
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- Authors
- Tang, S., Wang, X., Li, W., Yang, X., Li, Z., Liu, W., Li, C., Zhu, Z., Wang, L., Wang, J., Zhang, L., Sun, X., Zhi, E., Wang, H., Li, H., Jin, L., Luo, Y., Wang, J., Yang, S., & Zhang, F.
- Affiliations
- Shanghai Medical College of Fudan University (CN)
- Qingdao University (CN)
- Jiangsu Province Hospital (CN)
- Shanghai Jiao Tong University (CN)
- Fudan University (CN)
- Nanjing Medical University (CN)
- China Medical University (CN)
- Corresponding author
- Yang, Shenmin
- Zhang, Feng
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 100
- Issue
- 6
- Pages
- 854-864
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5473723
- OpenAlex
- W2617398306
- Cited by
- 304
- References
- 50
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 33 · 2023: 38 · 2022: 47 · 2021: 33 · 2020: 35 · 2019: 35 · 2018: 29 · 2017: 3
- FWCI
- 31.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Key Research and Development Program of China (2016YFC0905100, 2016YFC1000600)
- Maternal and Child Health Research Project of Jiangsu Province (F201521)
- National Natural Science Foundation of China (31625015, 31521003, 31571297)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- male infertility, sperm motility, compound heterozygosity, frameshift mutation, recessive mutations, Han Chinese men, unexplained male infertility
- MeSH terms
- Alleles, Animals, Base Sequence, Cytoskeletal Proteins, Disease Models, Animal, Humans, Infertility, Male, Male, Mice, Inbred C57BL, Mutation, Phenotype, Semen, Sperm Tail
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