HGNC Approved Gene Symbol: USP26
Cytogenetic location: Xq26.2 Genomic coordinates (GRCh38) : X:133,023,168-133,097,109 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26.2 | Spermatogenic failure, X-linked, 6 | 301101 | X-linked | 3 |
USP26 encodes a deubiquitinating enzyme expressed preferentially in testis (summary by Liu et al., 2021).
In a systematic search for genes expressed in mouse spermatogonia but not in somatic tissues, Wang et al. (2001) identified 25 genes, 19 of which were novel, that are expressed in only male germ cells. Of the 25 genes, 3 are Y-linked and 10 are X-linked, indicating that the X chromosome has a predominant role in pre-meiotic stages of mammalian spermatogenesis. One of the novel X-linked mouse genes identified was ubiquitin-specific protease-26, which encodes a predicted protein containing his and cys domains that are conserved among deubiquitinating enzymes. Usp26 shows testis-specific expression. Wang et al. (2001) identified an orthologous, full-length human USP26 cDNA sequence.
Using quantitative real-time PCR, Wosnitzer et al. (2014) detected USP26 mRNA in normal human testis and in human breast and thyroid cancer tissues, but not in normal human brain or murine epididymis, kidney, or liver. Protein dot blot analysis of non-testis normal human tissues detected ubiquitous USP26 expression, with highest expression in cervix and skin, and lowest expression in thyroid. USP26 protein was variably expressed in all tumor tissues examined, with significant overexpression in thyroid cancer. Immunohistochemical analysis of normal human testis detected USP26 in nucleus and cytoplasm of Leydig cells and in early spermatogonia. USP26 was also detected in breast myoepithelial cells and secretory luminal cells, as well as in cytoplasm and perinuclear areas of thyroid follicular cells. Western blot analysis of human testis detected USP26 at an apparent molecular mass of 100 kD.
Stouffs et al. (2005) noted that the USP26 gene mRNA sequence is 2,794 bp long and comprises 1 exon.
By radiation hybrid analysis, Wang et al. (2001) mapped the human USP26 gene to the X chromosome. Stouffs et al. (2005) reported that the USP26 gene maps to chromosome Xq26.2 (Genbank NM_031907).
X-Linked Spermatogenic Failure 6
In 2 unrelated Chinese men with infertility due to asthenoteratozoospermia (SPGFX6; 301101), Liu et al. (2021) identified hemizygosity for missense mutations in the USP26 gene, R825G (300309.0001) and N799S (300309.0002). The mutations, which were confirmed by Sanger sequencing, were shown to be inherited from the unaffected mother in each family. Neither variant was found in the 1000 Genomes Project database, but both were present at very low minor allele frequency in the gnomAD database. Functional analysis showed markedly reduced USP26 mRNA and protein levels in patient sperm.
Associations Pending Confirmation
In 776 Han Chinese men with nonobstructive azoospermia, Ma et al. (2016) screened 654 infertility-related genes, including USP26. In 2 azoospermic men with spermatogenic arrest at the spermatocyte stage, they identified a c.1082G-A (chrX:133,027,091G-A; GRCh37) transition in the USP26 gene, resulting in an R344W substitution. The mutation was not detected in 709 fertile Han Chinese men but was found at an allele frequency of 0.0007588 in the ExAC database. Coimmunoprecipitation analysis showed that the R344W mutant did not bind to the androgen receptor (AR), and the mutant showed significantly decreased deubiquitinating activity in HeLa cells compared to wildtype. In addition, the R344W mutant eliminated the inhibitory effect of USP26 on AR activity in both HeLa and TM4 cells. Ma et al. (2016) concluded that the R344W variant in USP26 is associated with nonobstructive azoospermia, likely through disruption of AR function.
Exclusion Studies
USP26 is specifically expressed in testis tissue and is a potential infertility gene. In 8 of 111 patients (7.2%) with Sertoli cell-only syndrome (305700), Stouffs et al. (2005) found the same 3 changes of the nucleotide sequence of USP26, all on the same allele: an insertion, 370_371insACA, resulting in the insertion of a threonine residue between codon 123 and 124; a 494T-C transition resulting in a leu165-to-ser substitution (L165S); and a 1423C-T transition resulting in a his475-to-tyr substitution (H475Y). These changes were not found in 152 fertile controls or 32 patients with azoospermia with maturation arrest (270960). DNA from other family members was not available for segregation analysis, nor was testicular tissue available for expression analysis. Stouffs et al. (2005) suggested that these changes might be involved in male infertility or increase the risk of male infertility.
Using a restriction reaction to detect the 494T-C change in the USP26 gene, Stouffs et al. (2006) analyzed 146 Caucasian patients with cryptozoospermia or oligozoospermia and 202 controls. The variant was only detected in 1 man from the control group, who was diagnosed with obstructive azoospermia but who had normal spermatogenesis on testicular biopsy; sequencing confirmed the presence of the other 2 variants in this individual. Stouffs et al. (2006) concluded that the previously identified cluster of changes does not affect spermatogenesis per se.
Ravel et al. (2006) demonstrated that 2 of the changes identified by Stouffs et al. (2006) in the USP26 gene, 494T-C and 370_371insACA, correspond to the ancestral sequence of the gene, and that the USP26 haplotype is present in significant frequencies in sub-Saharan African and South and East Asian populations, including in individuals with known fertility. Ravel et al. (2006) concluded that the allele is not associated with infertility.
Zhang et al. (2015) performed a USP cleavage assay with 5 frequently reported variants in the USP26 gene, including c.363_364insACA (previously designated 370_371insACA), c.494T-C, c.1090C-T, c.1423C-T, and c.1737G-A (NM_031907.1). The mutants showed the same activity as wildtype, both when tested individually and when tested as a construct containing the 3 variants (c.363_364insACA, c.494T-C, and c.1423C-T) that have been found in a cluster. The authors also performed a metaanalysis of 10 case-control studies involving a total of 1,716 patients and 2,597 controls but found no significant association between USP26 variants and male infertility.
In a 30-year-old Chinese man (H002) with infertility due to asthenoteratozoospermia (SPGFX6; 301101), Liu et al. (2021) identified hemizygosity for a c.2473C-G transversion (c.2473C-G, NM_031907.3) in the USP26 gene, resulting in an arg825-to-gly (R825G) substitution at a conserved residue. The mutation, which was confirmed by Sanger sequencing and was shown to be inherited from his unaffected mother, was not found in the 1000 Genomes Project database. However, it was present at very low minor allele frequency in the gnomAD database (0.0001444 in East Asians, 0.00001093 overall). RT-qPCR and immunoblot assays of patient sperm showed markedly reduced USP26 mRNA and protein levels compared to control sperm, and immunostaining showed that USP26 was almost absent from patient sperm.
In a 34-year-old Chinese man (H042) with infertility due to asthenoteratozoospermia (SPGFX6; 301101), Liu et al. (2021) identified hemizygosity for a c.2396A-G transition (c.2396A-G, NM_031907.3) in the USP26 gene, resulting in an asn799-to-ser (N799S) substitution at a well-conserved residue. The mutation, which was confirmed by Sanger sequencing and was shown to be inherited from his unaffected mother, was not found in the 1000 Genomes Project database. However, it was present at very low minor allele frequency in the gnomAD database (0.00007219 in East Asians, 0.000005463 overall). RT-qPCR and immunoblot assays of patient sperm showed markedly reduced USP26 mRNA and protein levels compared to control sperm, and immunostaining showed that USP26 was almost absent from patient sperm.
Liu, C., Shen, Y., Shen, Q., Zhang, W., Wang, J., Tang, S., Wu, H., Tian, S., Cong, J., He, X., Jin, L., Zhang, F., Jiang, X., Cao, Y. Novel mutations in X-linked, USP26-induced asthenoteratozoospermia and male infertility. Cells 10: 1594, 2021. [PubMed: 34202084] [Full Text: https://doi.org/10.3390/cells10071594]
Ma, Q., Li, Y., Guo, H., Li, C., Chen, J., Luo, M., Jiang, Z., Li, H., Gui, Y. A novel missense mutation in USP26 gene is associated with nonobstructive azoospermia. Reprod. Sci. 23: 1434-1441, 2016. [PubMed: 27089915] [Full Text: https://doi.org/10.1177/1933719116641758]
Ravel, C., El Houate, B., Chantot, S., Lourenco, D., Dumaine, A., Rouba, H., Bandyopadahyay, A., Radhakrishna, U., Das, B., Sengupta, S., Mandelbaum, J., Siffroi, J. P., McElreavey, K. Haplotypes, mutations and male fertility: the story of the testis-specific ubiquitin protease USP26. Molec. Hum. Reprod. 12: 643-646, 2006. [PubMed: 16888075] [Full Text: https://doi.org/10.1093/molehr/gal063]
Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A., Liebaers, I. Possible role of USP26 in patients with severely impaired spermatogenesis. Europ. J. Hum. Genet. 13: 336-340, 2005. [PubMed: 15562280] [Full Text: https://doi.org/10.1038/sj.ejhg.5201335]
Stouffs, K., Lissens, W., Tournaye, H., Van Steirteghem, A., Liebaers, I. Alterations of the USP26 gene in Caucasian men. Int. J. Androl. 29: 614-617, 2006. [PubMed: 17121659] [Full Text: https://doi.org/10.1111/j.1365-2605.2006.00708.x]
Wang, P. J., McCarrey, J. R., Yang, F., Page, D. C. An abundance of X-linked genes expressed in spermatogonia. Nature Genet. 27: 422-426, 2001. [PubMed: 11279525] [Full Text: https://doi.org/10.1038/86927]
Wosnitzer, M. S., Mielnik, A., Dabaja, A., Robinson, B., Schlegel, P. N., Paduch, D. A. Ubiquitin specific protease 26 (USP26) expression analysis in human testicular and extragonadal tissues indicates diverse action of USP26 in cell differentiation and tumorigenesis. PLoS One 9: e98638, 2014. Note: Electronic Article. [PubMed: 24922532] [Full Text: https://doi.org/10.1371/journal.pone.0098638]
Zhang, W., Liu, T., Mi, Y.-J., Yue, L.-D., Wang, J.-M., Liu, D.-W., Yan, J., Tian, Q. B. Evidence from enzymatic and meta-analyses does not support a direct association between USP26 gene variants and male infertility. Andrology 3: 271-279, 2015. [PubMed: 25755145] [Full Text: https://doi.org/10.1111/andr.295]