Pathogenic variations in Germ Cell Nuclear Acidic Peptidase (GCNA) are associated with human male infertility

Arafat, Maram; Kleiman, Sandra E.; AbuMadighem, Ali; Zeadna, Atif; Levitas, Eliahu; Vardi, Iris Har; Barda, Shimi; Lehavi, Ofer; Hauser, Ron; Lunenfeld, Eitan; Huleihel, Mahmoud; Gershoni, Moran; Parvari, Ruti

doi:10.1038/s41431-021-00946-2

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…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%

“…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: Gcna Supports Long Term Gametogenesis In Male Micementioning

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: 99%

Section: Gcna Supports Long Term Gametogenesis In Male Micementioning

confidence: 99%

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

Ribeiro

Crossan

2022

Preprint

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“…Because the pipeline used produces a Variant Call Format (VCF) text file, which stores all genomic positions with sequence variations, we refer to this procedure as the VCF method. For this method, variant calling was conducted as we previously described [ 15 ]. Briefly, adapter sequences and low-quality tails of reads were removed with the software Trimmomatic [ 16 ].…”

Section: Methodsmentioning

confidence: 99%

Comparing BeadChip and WGS Genotyping: Non-Technical Failed Calling Is Attributable to Additional Variation within the Probe Target Sequence

Gershoni

Shirak

Raz

et al. 2022

Genes

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Microarray-based genomic selection is a central tool to increase the genetic gain of economically significant traits in dairy cattle. Yet, the effectivity of this tool is slightly limited, as estimates based on genotype data only partially explain the observed heritability. In the analysis of the genomes of 17 Israeli Holstein bulls, we compared genotyping accuracy between whole-genome sequencing (WGS) and microarray-based techniques. Using the standard GATK pipeline, the short-variant discovery within sequence reads mapped to the reference genome (ARS-UCD1.2) was compared to the genotypes from Illumina BovineSNP50 BeadChip and to an alternative method, which computationally mimics the hybridization procedure by mapping reads to 50 bp spanning the BeadChip source sequences. The number of mismatches between the BeadChip and WGS genotypes was low (0.2%). However, 17,197 (40% of the informative SNPs) had extra variation within 50 bp of the targeted SNP site, which might interfere with hybridization-based genotyping. Consequently, with respect to genotyping errors, BeadChip varied significantly and systematically from WGS genotyping, introducing null allele-like effects and Mendelian errors (<0.5%), whereas the GATK algorithm of local de novo assembly of haplotypes successfully resolved the genotypes in the extra-variable regions. These findings suggest that the microarray design should avoid polymorphic genomic regions that are prone to extra variation and that WGS data may be used to resolve erroneous genotyping, which may partially explain missing heritability.

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“…Male factor infertility is frequently of unknown aetiology. Arafat and colleagues identify variants in GCNA in association with low sperm count and impared sperm motility [11].Not all (rare) disease is monogenic (that is explained by variants in a single gene). In an Indian study, 14 families with clinical phenotypes associated with causal variants in more than one mendelian disease gene are reported [12].…”

mentioning

confidence: 99%

“…Male factor infertility is frequently of unknown aetiology. Arafat and colleagues identify variants in GCNA in association with low sperm count and impared sperm motility [11].…”

mentioning

confidence: 99%

Genomics elucidates both common and rare disease aetiology

McNeill

2021

Eur J Hum Genet

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Welcome to the final issue of European Journal of Human Genetics for 2021. We close the year with a range of interesting and informative papers. Birth defects (congenital anomalies) affect many thousands of neonates every year; yet the aetiology of many of them remains unresolved. Schreiner et al review what is known about the genomic basis of congenital diaphragmatic hernia (CDH) [1]. Around 10% of cases of CDH are associated with a copy number variant. Implicated pathways include NRF2 and vitamin A homeostasis. In contrast to common malformations, the genetic basis of rare disease continues to be elucidated with more and more causal genes identified annually [2][3][4]. Guo and colleagues identify variants in SLIRP as a novel cause of mitochondrial disease [5]. In this issue, variants in IMPDH2 are associated with dystonia in a large family [6]; IMPDH2 acts in the dopamine synthesis pathway previously implicated in the aetiology of dystonia. Of course, even with modern technology there remain patients for whom a molecular genetic diagnosis remains elusive. Pham et al demonstrate that variants in DLK4 are not responsible for Silver-Russell-Syndrome [7].Kawasaki disease is a paediatric vasculitis with a risk of coronary artery involvement. In this month's EJHG Hoggart et al identify a potential genetic risk factor for coronary artery involvement in Kawasaki disease [8]. For many genetic diseases, little is known about population epidemiology. In a study of malignant hyperthermia gene variants in Iceland, it was estimated that 1/ 1450 Icelanders carry an actionable variant in a malignant hyperthermia gene [9]. Keratoconus (defined as noninflammatory corneal ectasia) is of uncertain aetiology. Fransen et al identify a shared genetic link between keratoconus and the connective tissue disease Ehlers-Danlos syndrome [10]. Male factor infertility is frequently of unknown aetiology. Arafat and colleagues identify variants in GCNA in association with low sperm count and impared sperm motility [11].Not all (rare) disease is monogenic (that is explained by variants in a single gene). In an Indian study, 14 families with clinical phenotypes associated with causal variants in more than one mendelian disease gene are reported [12]. The clinical consequences were described as blended phenotypes, a mild phenotype from gene A being obscured by a severe phenotype from gene B or 2 distinct phenotypes in the same patient. Undoubtedly such multilocus variation has the potential to contribute to phenotype variability in genetic diseases. Sharing information on pathogenic gene variants is crucial to help clinical reporting. The updated LOVD3 platform provides one mechanism for doing so [13].All genomics research must be ethically approved and adhere to conditions set by the relevant committees. But do research ethics committees have sufficient understanding to review and grant permission for ethically robust genomics research? A study of Australian research ethics committees highlights a potential need for extra training for committee ...

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Pathogenic variations in Germ Cell Nuclear Acidic Peptidase (GCNA) are associated with human male infertility

Cited by 12 publications

References 44 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

Comparing BeadChip and WGS Genotyping: Non-Technical Failed Calling Is Attributable to Additional Variation within the Probe Target Sequence

Genomics elucidates both common and rare disease aetiology

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