Alternative titles; symbols
HGNC Approved Gene Symbol: USP9Y
Cytogenetic location: Yq11.221 Genomic coordinates (GRCh38): Y:12,701,231-12,860,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Yq11.221 | Spermatogenic failure, Y-linked, 2 | 415000 | Y-linked | 3 |
Jones et al. (1996) reported that an expressed sequence tag (EST 221) derived from human adult testis shares homology with the Drosophila fat facets (faf) gene. They detected related sequences on both the human X and Y chromosomes. They used EST 221 to derive clones covering the complete open reading frame of the X-specific locus they termed DFFRX (300072). Y-specific cDNA clones were derived and the corresponding Y-specific locus designated DFFRY. Over the 2 regions corresponding to nucleotides 6 to 1901 and nucleotides 5815 to 7907 of the DFFRX sequence, the X- and Y-specific sequences share 91% and 88% identity, respectively. Both putative gene products contain conserved cysteine and histidine domains that have been described in ubiquitin C-terminal hydrolases (e.g., 191342). Multiple stop codons in the 3-prime region of DFFRY suggested that the Y locus may encode a truncated product or may represent a nonfunctional pseudogene. Jones et al. (1996) detected expression of both DFFRX and DFFRY in developing human tissues. They found also that sequences detected by the EST 221 were widely expressed in adult human tissues.
Brown et al. (1998) noted that the coding regions of the DFFRY and DFFRX genes show 89% identity at the nucleotide level. In common with DFFRX, the potential amino acid sequence of DFFRY contains the conserved cys and his domains characteristic of ubiquitin C-terminal hydrolases. The human DFFRY mRNA is expressed in a wide range of adult and embryonic tissues, including testis, whereas the homologous mouse Dffry gene is expressed specifically in the testis.
Jones et al. (1996) mapped DFFRY to Yq11.2 by Southern analysis.
Brown et al. (1998) found that 3 azoospermic male patients had deletion of DFFRY from the Y chromosome. Two patients had a testicular phenotype that resembled Sertoli cell-only type I (see 400042), and the third (patient 'Sayer') had diminished spermatogenesis (see 400005.0002). In all 3 patients, the deletions extended from close to the 3-prime end into the gene, removing the entire coding sequence of DFFRY. Brown et al. (1998) showed that the mouse Dffry gene maps to the Sxr-b deletion interval on the shorter arm of the mouse Y chromosome and that its expression in mouse testis can first be detected between 7.5 and 10.5 days after birth when type A and B spermatogonia and preleptotene and leptotene spermatocytes are present.
Sargent et al. (1999) refined the deletion breakpoints in 4 patients with AZFa male infertility. All patients had USP9Y and an anonymous EST, AZFaT1, deleted in their entirety, and 3 patients also had DBY (400010) deleted. The 3 patients with AZFaT1, USP9Y, and DBY deleted showed a severe Sertoli cell-only type I phenotype, whereas the patient who had retained DBY (SAYER, originally reported by Brown et al., 1998) showed a milder oligozoospermic phenotype (see 400005.0002). RT-PCR analysis of mouse testis RNA showed that Dby is expressed primarily in somatic cells, while Usp9y is expressed specifically in testis in a germ cell-dependent fashion.
Sun et al. (1999) were the first to trace spermatogenic failure to a point mutation in a Y-linked gene or to a deletion of a single Y-linked gene. They sequenced the AZFa (see 415000) region of the Y chromosome and identified 2 previously described functional genes: USP9Y and DBY (400010). Screening of the 2 genes in 576 infertile and 96 fertile men revealed several sequence variants, most of which appeared to be heritable and of little functional consequence. They found 1 de novo mutation in USP9Y (400005.0001): a 4-bp deletion in the splice donor site, causing an exon to be skipped and protein truncation. This mutation was present in a man with nonobstructive azoospermia, but was absent in his fertile brother, suggesting that the USP9Y mutation caused spermatogenic failure. Sun et al. (1999) also identified a single gene deletion associated with spermatogenic failure, again involving USP9Y, by reanalyzing the third patient (SAYER) from Brown et al. (1998); see 400005.0002.
Foresta et al. (2000) described a complete sequence map of the AZFa region, the genomic structure of AZFa genes, and their deletion analysis in 173 infertile men with well-defined spermatogenic alterations. Deletions were found in 9 patients: DBY alone was deleted in 6, USP9Y alone in one (400005.0002), and there was one each with USP9Y-DBY or DBY-UTY (400009) missing. No patients solely lacked UTY. Patients lacking DBY exhibited either Sertoli cell-only syndrome or severe hypospermatogenesis. Expression analysis of AZFa genes and their X homologs revealed ubiquitous expression for all of them except DBY; a shorter DBY transcript was expressed only in testis. The authors suggested that DBY plays a key role in the spermatogenic process.
In a normospermic man and his brother and father, Luddi et al. (2009) identified a deletion in the AZFa region that encompassed the USP9Y gene (400005.0002). The authors concluded that USP9Y is not essential for normal sperm production and fertility in humans.
In a worldwide sample of human Y chromosomes, Thomson et al. (2000) analyzed DNA sequence variation at 3 Y chromosome genes: SMCY (KDM5D; 426000), DBY, and DFFRY. They used denaturing high-performance liquid chromatography to determine sequence variation at each locus. They focused on estimating the expected time to the most recent common ancestor (TMRCA) and the expected ages of certain mutations with interesting geographic distributions. Although the geographic structure of the inferred haplotype tree was reminiscent of that obtained for other loci (the root is in Africa, and most of the oldest non-African lineages are Asian), the expected TMRCA was found to be remarkably short, on the order of 50,000 years. They estimated that the spread of Y chromosomes out of Africa was much more recent than previously thought. Their data also indicated substantial population growth in the effective number of different human Y chromosomes.
By use of denaturing HPLC, Shen et al. (2000) screened the DFFRY, SMCY, DBY, and UTY1 genes for polymorphic markers in males representative of the 5 continents. Nucleotide diversity was found in the coding regions of 3 of the genes but was not observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher than those for coding regions. Pairwise nucleotide mismatch distributions dated the occurrence of population expansion to approximately 28,000 years ago.
Mendez et al. (2016) compared approximately 120 kb of exome-captured Y-chromosome DNA from a Neandertal male from Spain with orthologous chimpanzee and modern human sequences. They found support for a model that placed the Neandertal lineage as an outgroup to modern human Y chromosomes, including A00, the highly divergent basal haplogroup. The authors estimated that the TMRCA of Neandertal and modern human Y chromosomes was approximately 588,000 years ago, approximately 2 times longer than the TMRCA of A00 and other extant modern human Y-chromosome lineages. The estimate suggested that the Y-chromosome divergence mirrored the population divergence of Neandertals, whose Y sequence is not found in modern humans, and modern human ancestors. Notable coding differences between Neandertal and modern human Y chromosomes included potentially damaging changes to PCDH11Y (400022), TMSB4Y (400017), USP9Y, and KDM5D. Three of these changes occurred in genes that produce male-specific minor histocompatibility (H-Y) antigens that may elicit a maternal immune response during gestation. The authors hypothesized that the incompatibilities at 1 or more of these genes may have played a role in the reproductive isolation of the 2 groups.
In an azoospermic (415000) and infertile but otherwise healthy male, Sun et al. (1999) discovered a 4-bp deletion in the splice donor site of USP9Y intron 7. The deletion was not present in the man's brother, who had fathered 2 children. The men were found to share a rare Y haplotype not reported previously. These findings suggested that the 2 men inherited the same Y chromosome apart from what was evidently a de novo USP9Y mutation in the azoospermic man. The splice site deletion predicted the skipping of exon 7, shifting the reading frame and causing USP9Y to be truncated by approximately 90%. This was confirmed by sizing and sequencing of the RT-PCR product in the proband and his brother. The splice site/frameshift mutation, falling near the 5-prime end of the USP9Y coding sequence, was expected to result in the loss of USP9Y function. A testicular biopsy of the patient revealed hypospermatogenesis with spermatogenic arrest.
In a patient with hypospermatogenesis (400042), previously studied by Ferlin et al. (1999), Foresta et al. (2000) reported a deletion of the entire USP9Y coding region. The testicular phenotype was identical to that of a patient (SAYER), earlier reported by Brown et al. (1998) and Sargent et al. (1999), whose deletion encompassed both USP9Y and AZFaT1 (see 400042). Foresta et al. (2000) suggested that the phenotype of patient SAYER, whose testicular biopsy revealed small to moderate numbers of mature spermatozoa and occasional tubules with only spermatids, spermatocytes, or spermatogonia, was due solely to the deletion of USP9Y.
In a 42-year-old man who underwent spermatologic and genetic analysis as part of an infertility analysis after his partner had a miscarriage, Luddi et al. (2009) identified a 513,594-bp deletion in the AZFa region of the Y chromosome, with breakpoints located approximately 320,521 bp upstream and 33,465 bp downstream of the USP9Y gene. Spermatologic analysis revealed mild asthenozoospermia, but all other sperm characteristics were within the normal range. His father and brother, who did not undergo spermatologic analysis, were also found to carry the deletion. The authors concluded that USP9Y is not essential for normal sperm production and fertility in humans.
Brown, G. M., Furlong, R. A., Sargent, C. A., Erickson, R. P., Longepied, G., Mitchell, M., Jones, M. H., Hargreave, T. B., Cooke, H. J., Affara, N. A. Characterisation of the coding sequence and fine mapping of the human DFFRY gene and comparative expression analysis and mapping to the Sxr-b interval of the mouse Y chromosome of the Dffry gene. Hum. Molec. Genet. 7: 97-107, 1998. [PubMed: 9384609] [Full Text: https://doi.org/10.1093/hmg/7.1.97]
Ferlin, A., Moro, E., Garolla, A., Foresta, C. Human male infertility and Y chromosome deletions: role of the AZF-candidate genes DAZ, RBM and DFFRY. Hum. Reprod. 14: 1710-1716, 1999. [PubMed: 10402373] [Full Text: https://doi.org/10.1093/humrep/14.7.1710]
Foresta, C., Ferlin, A., Moro, E. Deletion and expression analysis of AZFa genes on the human Y chromosome revealed a major role for DBY in male infertility. Hum. Molec. Genet. 9: 1161-1169, 2000. [PubMed: 10767340] [Full Text: https://doi.org/10.1093/hmg/9.8.1161]
Jones, M. H., Furlong, R. A., Burkin, H., Chalmers, I. J., Brown, G. M., Khwaja, O., Affara, N. A. The Drosophila developmental gene fat facets has a human homologue in Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2. Hum. Molec. Genet. 5: 1695-1701, 1996. Note: Erratum: Hum. Molec. Genet. 6: 334-335, 1997. [PubMed: 8922996] [Full Text: https://doi.org/10.1093/hmg/5.11.1695]
Luddi, A., Margollicci, M., Gambera, L., Serafini, F., Cioni, M., De Leo, V., Balestri, P., Piomboni, P. Spermatogenesis in a man with complete deletion of USP9Y. New Eng. J. Med. 360: 881-885, 2009. [PubMed: 19246359] [Full Text: https://doi.org/10.1056/NEJMoa0806218]
Mendez, F. L., Poznik, G. D., Castellano, S., Bustamante, C. D. The divergence of Neandertal and modern human Y chromosomes. Am. J. Hum. Genet. 98: 728-734, 2016. [PubMed: 27058445] [Full Text: https://doi.org/10.1016/j.ajhg.2016.02.023]
Sargent, C. A.., Boucher, C. A., Kirsch, S., Brown, G., Weiss, B., Trundley, A., Burgoyne, P., Saut, N., Durand, C., Levy, N., Terriou, P., Hargreave, T., Cooke, H., Mitchell, M., Rappold, G. A., Affara, N. A. The critical region of overlap defining the AZFa male infertility interval of proximal Yq contains three transcribed sequences. J. Med. Genet. 36: 670-677, 1999. [PubMed: 10507722]
Shen, P., Wang, F., Underhill, P. A., Franco, C., Yang, W.-H., Roxas, A., Sung, R., Lin, A. A., Hyman, R. W., Vollrath, D., Davis, R. W., Cavalli-Sforza, L. L., Oefner, P. J. Population genetic implications from sequence variation in four Y chromosome genes. Proc. Nat. Acad. Sci. 97: 7354-7359, 2000. [PubMed: 10861003] [Full Text: https://doi.org/10.1073/pnas.97.13.7354]
Sun, C., Skaletsky, H., Birren, B., Devon, K., Tang, Z., Silber, S., Oates, R., Page, D. C. An azoospermic man with a de novo point mutation in the Y-chromosomal gene USP9Y. Nature Genet. 23: 429-432, 1999. [PubMed: 10581029] [Full Text: https://doi.org/10.1038/70539]
Thomson, R., Pritchard, J. K., Shen, P., Oefner, P. J., Feldman, M. W. Recent common ancestry of human Y chromosomes: evidence from DNA sequence data. Proc. Nat. Acad. Sci. 97: 7360-7365, 2000. [PubMed: 10861004] [Full Text: https://doi.org/10.1073/pnas.97.13.7360]