Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure

Hardy, Jimmaline J; Wyrwoll, Margot J.; McFadden, William M.; Malcher, Agnieszka; Rotte, Nadja; Pollock, Nijole; Munyoki, Sarah; Veroli, Maria Victoria; Houston, Brendan J; Xavier, Miguel J; Kasak, Laura; Punab, Margus; Laan, Maris; Kliesch, Sabine; Schlegel, Peter N.; Jaffe, Thomas; Hwang, Kathleen; Vukina, Josip; Brieño‐Enríquez, Miguel A.; Orwig, Kyle E.; Yanowitz, Judith L.; Buszczak, Michael; Veltman, Joris A.; Oud, Manon S; Nagirnaja, Liina; Olszewska, Marta; O'Bryan, Moira K; Conrad, Donald F.; Kurpisz, Maciej; Tüttelmann, Frank; Yatsenko, Alexander N.

doi:10.1007/s00439-021-02287-y

Cited by 30 publications

(25 citation statements)

References 55 publications

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“…These mutations may lead to loss of GCNA protein but it is worth nothing that some mutations occur within the IDR. Strikingly, histological analysis of testis biopsies from two patients with GCNA mutations revealed a Sertoli-cell only phenotype in these two men (Hardy et al, 2021). This result strongly suggests that GCNA in humans may preserve the SSC pool, like we characterise here in mice.…”

Section: Discussionmentioning

confidence: 95%

“…Although mutations in the GCNA locus have been associated with azoospermia in humans, the mechanism behind this is not understood (Arafat et al, 2021; Hardy et al, 2021). Therefore, we sought to define the aetiology of this defect using a previously generated Gcna knock-out mouse allele (Appendix Fig S1, Δ Exon 4 allele)(Carmell et al, 2016) (MGI ID: 5910931) JAX (stock ID: 031055).…”

Section: Resultsmentioning

confidence: 99%

“…Functionally, GCNA appears to be of crucial importance for the maintenance of the human male germ line. Indeed, two recent reports describe the phenotype of several azoospermic men carrying mutations in the GCNA locus (Arafat et al, 2021; Hardy et al, 2021). These mutations may lead to loss of GCNA protein but it is worth nothing that some mutations occur within the IDR.…”

Section: Discussionmentioning

confidence: 99%

“…Germ Cell Nuclear Acidic protein (GCNA) has been extensively used as a germ cell marker for almost thirty years (Enders and May, 1994; Tanaka et al, 1997). Recently, mutations in GCNA have been linked to azoospermia in humans, defining GCNA as a clinical determinant of human infertility (Arafat et al, 2021; Hardy et al, 2021). Despite this, little is known about the function in mammals of this evolutionarily conserved factor.…”

Section: Introductionmentioning

confidence: 99%

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GCNA is a histone binding protein required for spermatogonial stem cell maintenance

Ribeiro

Crossan

2022

Preprint

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Recycling and de-novo deposition of histones during DNA replication is a critical challenge faced by eukaryotic cells and is coordinated by histone chaperones. However, little is known about how tissue-specific histone chaperones function to maintain tissue homeostasis. Here we show that Germ Cell Nuclear Acidic protein (GCNA), a germ cell specific protein in adult mice, can bind histones and purified GCNA exhibits histone chaperone activity. GCNA associates with the DNA replication machinery and supports progression through S-phase in murine spermatogonial stem cells (SSCs). Whilst GCNA is dispensable for embryonic germ cell development, it is required for the maintenance of the SSC pool and for long-term production of sperm. Our work describes the role of a germ cell specific histone chaperone in SSCs maintenance in mice. These findings provide a mechanistic basis for the male infertility observed in patients carrying mutations in the GCNA locus.

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Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GCNA is a histone binding protein required for spermatogonial stem cell maintenance

Ribeiro

Crossan

2022

Preprint

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“…WES data were generated within the Male Reproductive Genomics (MERGE) study as previously published (Wyrwoll et al ., 2020) and were screened for variants in 230 candidate genes that have at least a limited level of evidence for being associated with male infertility according to a recent review (Houston et al ., 2021). We also included a screening in the recently published genes ADAD2, GCNA, MAJIN, MSH4 , MSH5, RAD21L1, RNF212, SHOC1, STAG3, SYCP2, TERB1, TERB2 , and TRIM71 , which are associated with non-obstructive azoospermia (Riera-Escamilla et al ., 2019; Krausz et al ., 2020; Schilit et al ., 2020; Hardy et al ., 2021; Salas-Huetos et al ., 2021; Torres-Fernández et al ., 2021; Wyrwoll et al ., 2021). We screened for rare (minor allele frequency [MAF] in gnomAD database < 0.01), possibly pathogenic variants (stop-, frameshift-, and splice site variants) with a read depth > 10x, that were detected in accordance with the reported mode of inheritance.…”

Section: Methodsmentioning

confidence: 99%

Stage-specific gene and transcript dynamics in human male germ cells

Siebert-Kuss

Krenz

Tekath

et al. 2022

Preprint

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Cell differentiation processes are highly dependent on cell stage-specific gene expression, including timely production of alternatively spliced transcripts. One of the most transcriptionally rich tissues is the testis, where the process of spermatogenesis, or generation of male gametes, takes place. To date, germ cell-specific transcriptome dynamics remain understudied due to limited transcript information emerging from short-read sequencing technologies. To fully characterize the transcriptional profiles of human male germ cells and to understand how the human spermatogenic transcriptome is regulated, we compared whole transcriptomes of men with different types of germ cells missing from their testis. Specifically, we compared the transcriptomes of testis lacking germ cells (Sertoli cell-only phenotype; SCO; n=3), with an arrest at the stage of spermatogonia (SPG; n=4), spermatocytes (SPC; n=3), and round spermatids (SPD; n=3), with the transcriptomes of testis with normal and complete spermatogenesis (Normal; n=3). We found between 839 and 4,138 differentially expressed genes (DEGs, log2 fold change ≥ 1) per group comparison, with the most prevalent changes observed between SPG and SPC arrest samples, corresponding to the entry into meiosis. We detected highly germ cell-type specific marker genes among the topmost DEGs of each group comparison. Moreover, applying state-of-the-art bioinformatic analysis we were able to evaluate differential transcript usage (DTU) during human spermatogenesis and observed between 1,062 and 2,153 genes with alternatively spliced transcripts per group comparison. Intriguingly, DEGs and DTU genes showed minimal overlap (< 8%), suggesting that stage-specific splicing is an additional layer of gene regulation in the germline. By generating the most complete human testicular germ cell transcriptome to date, we unravel extensive dynamics in gene expression and alternative splicing during human spermatogenesis.

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Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non‐hormonal Male Contraceptive Targets

Garcia,

Matzuk

2024

Molecular Reproduction Devel

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The development of novel non‐hormonal male contraceptives represents a pivotal frontier in reproductive health, driven by the need for safe, effective, and reversible contraceptive methods. This comprehensive review explores the genetic underpinnings of male fertility, emphasizing the crucial roles of specific genes and structural variants (SVs) identified through advanced sequencing technologies such as long‐read sequencing (LRS). LRS has revolutionized the detection of structural variants and complex genomic regions, offering unprecedented precision and resolution over traditional next‐generation sequencing (NGS). Key genetic targets, including those implicated in spermatogenesis and sperm motility, are highlighted, showcasing their potential as non‐hormonal contraceptive targets. The review delves into the systematic identification and validation of male reproductive tract‐specific genes, utilizing advanced transcriptomics and genomics studies with validation using novel knockout mouse models. We discuss the innovative application of small molecule inhibitors, developed through platforms like DNA‐encoded chemistry technology (DEC‐Tec), which have shown significant promise in preclinical models. Notable examples include inhibitors targeting serine/threonine kinase 33 (STK33), soluble adenylyl cyclase (sAC), cyclin‐dependent kinase 2 (CDK2), and bromodomain testis associated (BRDT), each demonstrating nanomolar affinity and potential for reversible and specific inhibition of male fertility. This review also honors the contributions of Dr. David L. Garbers whose foundational work has paved the way for these advancements. The integration of genomic, proteomic, and chemical biology approaches, supported by interdisciplinary collaboration, is poised to transform male contraceptive development. Future perspectives emphasize the need for continued innovation and rigorous testing to bring these novel contraceptives from the laboratory to clinical application, promising a new era of male reproductive health management.

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Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure

Cited by 30 publications

References 55 publications

GCNA is a histone binding protein required for spermatogonial stem cell maintenance

GCNA is a histone binding protein required for spermatogonial stem cell maintenance

Stage-specific gene and transcript dynamics in human male germ cells

Novel Genes of the Male Reproductive System: Potential Roles in Male Reproduction and as Non‐hormonal Male Contraceptive Targets

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