Alternative titles; symbols
HGNC Approved Gene Symbol: GCNA
Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38) : X:71,578,437-71,613,583 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.1 | Spermatogenic failure, X-linked, 4 | 301077 | X-linked | 3 |
By a combination of in silico and 'wet' experiments, Nolte et al. (2001) identified a novel gene, designated ACRC, within the torsion dystonia (DYT3; 314250) critical region on Xq13.1. They cloned an ACRC cDNA from a fetal brain cDNA library. ACRC encodes a predicted acidic nuclear protein of 691 amino acids with a characteristic repeat of 21 units of 8 to 10 amino acids. The protein contains several potential nuclear localization signals in the C terminus as well as putative N-glycosylation and phosphorylation sites. Northern blot analysis detected expression of a 3.2-kb ACRC transcript in all tissues tested, with highest expression in skeletal muscle.
Hardy et al. (2021) examined a single-cell RNA-seq dataset from cryopreserved normal adult human testis. Analysis of sequencing results from 35,941 transcripts derived from 13,597 cells indicated that GCNA RNA is expressed predominantly in spermatogonia. Using conserved germ cell markers to biologically annotate clusters of spermatogonia, the authors observed that GCNA RNA is primarily expressed in differentiating spermatogonia in humans. Immunohistochemical analysis of control testicular tissue demonstrated that GCNA protein is produced throughout spermatogenesis in normal adult human testis, from spermatogonia to elongated spermatids.
Nolte et al. (2001) determined that the ACRC gene contains at least 12 exons and spans 35.5 kb.
By sequence analysis, Nolte et al. (2001) identified the ACRC gene on chromosome Xq13.1 within the DYT3 critical region.
Based on its deduced nuclear localization and the deduced nature of the polypeptide, Nolte et al. (2001) suggested that the ACRC gene may play a role in chromatin structure.
X-Linked Spermatogenic Failure 4
Hardy et al. (2021) analyzed whole-exome sequencing data from a total of 2,225 infertile men with spermatogenic failure phenotypes ranging from cryptozoospermia to azoospermia, and identified 7 men with potentially significant variants in the GCNA gene (SPGFX4; 301077; see, e.g., 300369.0001). All 7 variants, which were confirmed by Sanger sequencing, had extremely low minor allele frequencies in the general male population, and 6 of the 7 were not found in an anonymous cohort of 5,784 Dutch biological fathers.
In an infertile Bedouin man with azoospermia due to maturation arrest at the spermatogonia stage, Arafat et al. (2021) identified hemizygosity for a nonsense mutation in the GCNA gene (E394X; 300369.0002) that was not found in public variant databases or in-house Bedouin controls. The authors also identified an Israeli Arab man with infertility due to oligoasthenoteratozoospermia who was hemizygous for an insertion/deletion mutation in GCNA (300369.0003).
In an infertile Algerian man with azoospermia due to premeiotic spermatogenic arrest, Kherraf et al. (2022) identified hemizygosity for a 1-bp deletion in the GCNA gene (300369.0004).
Exclusion Studies
Nolte et al. (2001) found no mutations in the transcribed portion of the ACRC gene in patients with X-linked dystonia-parkinsonism (DYT3; 314250).
In a 37-year-old Croatian man (M1410) with infertility due to azoospermia (SPGFX4; 301077), Hardy et al. (2021) identified hemizygosity for a 1-bp deletion (c.343del) in the GCNA gene, causing a frameshift predicted to result in a premature termination codon (Ala115ProfsTer7) within the SUMO-interacting domain. The deletion was not found in 5,784 Dutch biological fathers or in the gnomAD database. The patient had normal gonadotropin levels but a low testosterone level.
In a Bedouin man (patient 1) with infertility due to azoospermia (SPGFX4; 301077), Arafat et al. (2021) identified hemizygosity for a c.1180G-T transversion (c.1180G-T, NM_052957.3) in exon 8 of the GCNA gene, resulting in a glu394-to-ter (E394X) substitution within an intrinsically disordered region. Familial segregation was not reported. The E394X variant was not found in 69 Bedouin control exomes, in an in-house database of 500 control individuals from mixed Israeli populations, or in public variant databases. GCNA staining was present at low levels in patient spermatogonial cells, compared to control testes biopsies.
In an Israeli Arab man (patient 2) with infertility due to oligoasthenoteratozoospermia (SPGFX4; 301077), Arafat et al. (2021) identified hemizygosity for an insertion/deletion (c.653_654delinsGC, NM_052957.3) in exon 8 of the GCNA gene, resulting in a lys218-to-ser (L218S) substitution. The patient reported possible infertility in a brother, sister, and cousin, but familial segregation was not performed. The mutation resulted from 2 tandem point mutations, c.653A-G and c.654G-C, which were both found in the gnomAD database, at minor allele frequencies of 0.00005 and 0.0001, respectively. However, examination of gnomAD data indicated that the variants occurred together and that all reports for the pathogenic variations were in heterozygous women, with the MAF of the tandem event being less than 0.00005. The variations were not found in 80 fertile and 144 infertile oligo- or azoospermic Arab men. Staining with GCNA antibody was observed in the patient's testis biopsy at approximately the same intensity as a control biopsy. Multiple attempts at achieving pregnancy by intracytoplasmic sperm injection (ICSI) were unsuccessful.
In an Algerian man (P0137) with infertility due to premeiotic spermatogenic arrest (SPGFX4; 301077), Kherraf et al. (2022) identified hemizygosity for a 1-bp deletion (c.1507del, NM_052957.5) in the GCNA gene, causing a frameshift predicted to result in a premature termination codon (Glu504LysfsTer11). Familial segregation was not reported; the deletion was not found in the gnomAD database.
Arafat, M., Kleiman, S. E., AbuMadighem, A., Zeadna, A., Levitas, E., Vardi, I. H., Barda, S., Lehavi, O., Hauser, R., Lunenfeld, E., Huleihel, M., Gershoni, M., Parvari, R. Pathogenic variations in germ cell nuclear acidic peptidase (GCNA) are associated with human male infertility. Europ. J. Hum. Genet. 29: 1781-1788, 2021. [PubMed: 34413498] [Full Text: https://doi.org/10.1038/s41431-021-00946-2]
Hardy, J. J., Wyrwoll, M. J., Mcfadden, W., Malcher, A., Rotte, N., Pollock, N. C., Munyoki, S., Veroli, M. V., Houston, B. J., Xavier, M. J., Kasak, L., Punab, M., and 19 others. Variants in GCNA, X-linked germ-cell genome integrity gene, identified in men with primary spermatogenic failure. Hum. Genet. 140: 1169-1182, 2021. [PubMed: 33963445] [Full Text: https://doi.org/10.1007/s00439-021-02287-y]
Kherraf, Z.-E., Cazin, C., Bouker, A., Fourati Ben Mustapha, S., Hennebicq, S., Septier, A., Coutton, C., Raymond, L., Nouchy, M., Thierry-Mieg, N., Zouari, R., Arnoult, C., Ray, P. F. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia. Am. J. Hum. Genet. 109: 508-517, 2022. [PubMed: 35172124] [Full Text: https://doi.org/10.1016/j.ajhg.2022.01.011]
Nolte, D., Ramser, J., Niemann, S., Lehrach, H., Sudbrak, R., Muller, U. ACRC codes for a novel nuclear protein with unusual acidic repeat tract and maps to DYT3 (dystonia parkinsonism) critical interval in Xq13.1. Neurogenetics 3: 207-213, 2001. [PubMed: 11714101] [Full Text: https://doi.org/10.1007/s100480100120]