ArticleHuman genetics2021
Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure.
Article in Human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 36 citations in OpenAlex.
- ACRC/GCNA is an essential protease that repairs DNA-protein crosslinks during vertebrate development.Nucleic acids research · 2026Article
- Article
- Identification of missense DMC1 variants in males with non-obstructive azoospermia.Journal of assisted reproduction and genetics · 2025Article
- Epigenetic regulation by DNA methylation, histone modifications and chromatin remodeling complexes in controlling spermatogenesis and their dysfunction with male infertility.Cellular and molecular life sciences : CMLS · 2025Review
- Establishment and clinical significance of genetic factor screening method for patients with nonobstructive azoospermia based on whole exon sequencing technology.Translational andrology and urology · 2025Article
- Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non-hormonal Male Contraceptive Targets.Molecular reproduction and development · 2024Review
- Frequency, morbidity and equity - the case for increased research on male fertility.Nature reviews. Urology · 2024Review
- Effects ofHuman reproduction open · 2024Article
- ESX1 gene as a potential candidate responsible for male infertility in nonobstructive azoospermia.Scientific reports · 2023Article
- In vivo versus in silico assessment of potentially pathogenic missense variants in human reproductive genes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- A pathogenic variant in the uncharacterizedHGG advances · 2023Article
- GCNA is a histone binding protein required for spermatogonial stem cell maintenance.Nucleic acids research · 2023Article
- Transcriptome analyses in infertile men reveal germ cell-specific expression and splicing patterns.Life science alliance · 2023Article
- Genomic study ofFrontiers in genetics · 2023Article
- Application of single-cell RNA sequencing on human testicular samples: a comprehensive review.International journal of biological sciences · 2023Review
- Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia.Andrology · 2022Article
- The piRNA-pathway factor FKBP6 is essential for spermatogenesis but dispensable for control of meiotic LINE-1 expression in humans.American journal of human genetics · 2022Article
- Genomic testing for copy number and single nucleotide variants in spermatogenic failure.Journal of assisted reproduction and genetics · 2022Article
- Large-scale analyses of the X chromosome in 2,354 infertile men discover recurrently affected genes associated with spermatogenic failure.American journal of human genetics · 2022Article
- Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia.American journal of human genetics · 2022Article
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Authors and funding
32 authors at 12 institutions in 8 countries.
Funding
Abstract
Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a potentially significant single-nucleotide variant (SNV) in X-linked germ-cell nuclear antigen (GCNA). Together with a larger follow-up study (n = 2049), 7 likely clinically relevant GCNA variants were identified. GCNA is critical for genome integrity in male meiosis and knockout models exhibit impaired spermatogenesis and infertility. Single-cell RNA-seq and immunohistochemistry confirm human GCNA expression from spermatogonia to elongated spermatids. Five identified SNVs were located in key functional regions, including N-terminal SUMO-interacting motif and C-terminal Spartan-like protease domain. Notably, variant p.Ala115ProfsTer7 results in an early frameshift, while Spartan-like domain missense variants p.Ser659Trp and p.Arg664Cys change conserved residues, likely affecting 3D structure. For variants within GCNA's intrinsically disordered region, we performed computational modeling for consensus motifs. Two SNVs were predicted to impact the structure of these consensus motifs. All identified variants have an extremely low minor allele frequency in the general population and 6 of 7 were not detected in > 5000 biological fathers. Considering evidence from animal models, germ-cell-specific expression, 3D modeling, and computational predictions for SNVs, we propose that identified GCNA variants disrupt structure and function of the respective protein domains, ultimately arresting germ-cell division. To our knowledge, this is the first study implicating GCNA, a key genome integrity factor, in human male infertility.
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