Alternative titles; symbols
HGNC Approved Gene Symbol: DDX3Y
Cytogenetic location: Yq11.221 Genomic coordinates (GRCh38) : Y:12,903,999-12,920,478 (from NCBI)
DEAD (asp-glu-ala-asp)-box RNA helicases, such as DDX3Y, are associated with many processes in the life of an RNA molecule, ranging from synthesis to degradation. They rearrange inter- or intramolecular RNA structures or RNA-protein complexes, and all contain the same structurally conserved core element characterized by 7 peptide domains conserved from yeast to human. This core element is flanked by divergent N- and C-terminal sequences that determine the specific function of each RNA helicase. The DDX3Y gene is located on the Y chromosome in the azoospermia factor a (AZFa; see 415000) region, deletion of which is a major cause of Sertoli cell-only syndrome (400042). DBY has a structural homolog, DDX3X (300160), located on the short arm of the X chromosome (Ditton et al., 2004).
The nonrecombining portion of the Y chromosome (the NRY) makes up 95% of the length of the Y chromosome. To identify genes located in the NRY, Lahn and Page (1997) isolated testis cDNAs that hybridized specifically to Y-chromosomal DNA. The cDNAs represented 12 novel genes or gene families. Lahn and Page (1997) grouped these 12 and several previously identified NRY genes into 2 classes. One group consisted of gene families expressed specifically in testis. A second class contained 5 genes that were expressed in many tissues. These housekeeping genes have homologs on the X chromosome that escape X inactivation. The authors suggested that these 5 genes represent cases where gene expression is maintained at comparable levels in males and females by preservation of homologous genes on both the X and the NRY, with male and female cells expressing both copies of each gene. They considered members of this group of NRY genes to be candidate genes for Turner syndrome. Lahn and Page (1997) identified DBY as the NRY-linked homolog of DBX (DDX3X). Northern blot analysis revealed that DBY was expressed in all human tissues tested, and that testis contained an additional smaller mRNA.
Ditton et al. (2004) found widespread transcription of both DBY and its X homolog, DBX, in each tissue analyzed, although predominantly in testis tissue. However, translation of DBY was detected only in the male germline, whereas DBX protein was expressed in all tissues analyzed. In testis tissue sections, DBY protein was found predominantly in spermatogonia, whereas DBX protein was expressed after meiosis in spermatids. Ditton et al. (2004) concluded that although both RNA helicases are structurally similar, they have diverged functionally to fulfill different roles in RNA metabolism of human spermatogenesis. They suggested that deletion of the DBY gene is the most likely cause of the severe testicular pathology observed in men with AZFa deletions.
Kretschmann et al. (2019) found that intercellular transfer of mouse and human DBY required interaction with HSC70 (HSPA8; 600816) through the conserved KFERQ-like motif of DBY. After binding HSC70, cytosolic DBY was recruited to extracellular vesicles of endosomal origin. These vesicles functioned as antigen carriers between viable cells to deliver DBY in a manner independent of cell-cell contact.
Role of DDX3Y in Spermatogenesis
Using a combination of proteomics, cytology, and functional analysis in C. elegans, Chu et al. (2006) reduced 1,099 proteins copurified with spermatogenic chromatin to 132 proteins for functional analysis. Reduction of gene function through RNA interference coupled with protein localization studies revealed conserved spermatogenesis-specific proteins vital for DNA compaction, chromosome segregation, and fertility. This strategy to find fertility factors conserved from C. elegans to mammals achieved its goal: of mouse gene knockouts corresponding to nematode proteins, 37% (7 of 19) cause male sterility. This list includes PPP1CC (176914), H2AX (601772), SON (182465), TOP1 (126420), DDX4 (605281), DBY, and CENPC (117141).
HY Antigens Encoded by DDX3Y
Using COS cells to express candidate Y chromosome genes and mouse dendritic cells for antigenic presentation, Scott et al. (2000) determined that Dby expresses 2 major histocompatibility complex (MHC) class II-restricted minor histocompatibility HY determinants. No stimulatory activity was found with these epitopes in cells transfected with Smcy (426000) or Uty, both of which express MHC class I-restricted epitopes.
Chen et al. (2004) identified the T-cell receptor contact sites of the dominant epitope of the Dby gene product and designed an altered peptide ligand (arg490 to his) that delivered incomplete signals to naive T cells from A1 x RAG1 (179615) -/- mice transgenic for a complementary T-cell receptor. Administration of this altered peptide ligand to female transgenic mice polarized T cells toward a regulatory phenotype, achieving a form of dominant tolerance to male skin grafts that was capable of resisting rejection by naive lymphocytes. Chen et al. (2004) proposed that incomplete signaling through the T-cell receptor may establish a network of T-regulatory cells that could be harnessed in the service of transplantation tolerance.
Rosinski et al. (2008) found that an HLAB*2705 HY antigen encoded by DDX3Y was recognized by a CD8 (see 186910)-positive cytotoxic lymphocyte (CTL) clone isolated from a male who had received a hematopoietic cell graft from his HLA-identical sister. The antigenic peptide is a decamer that differs from the homologous DDX3X peptide at 4 positions. PCR and CTL recognition assays detected DDX3Y expression in all myeloid and lymphoid cells possessing a Y chromosome. The CTL clones blocked engraftment of acute leukemia in immunodeficient mice, suggesting that such cells may contribute to graft-versus-leukemia activity after female-to-male hematopoietic cell transplantation.
By analysis of a panel of partial Y chromosomes, Lahn and Page (1997) mapped the DBY gene to region 5C on the long of arm of the Y chromosome. Three other single-copy genes with X-linked homologs, DFFRY (USP9Y; 400005), UTY (400009), and TB4Y (400017), map to the same region of the NRY.
Ditton et al. (2004) stated that the DDX3Y gene maps to chromosome Yq11.21.
Foresta et al. (2000) reported 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 only in 1, and 1 each with USP9Y-DBY or DBY-UTY 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.
By use of denaturing HPLC, Shen et al. (2000) screened the DBY, SMCY, DFFRY, 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.
Chen, T.-C., Waldmann, H., Fairchild, P. J. Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby. J. Clin. Invest. 113: 1754-1762, 2004. [PubMed: 15199410] [Full Text: https://doi.org/10.1172/JCI20569]
Chu, D. S., Liu, H., Nix, P., Wu, T. F., Ralston, E. J., Yates, J. R., III, Meyer, B. J. Sperm chromatin proteomics identifies evolutionarily conserved fertility factors. Nature 443: 101-105, 2006. [PubMed: 16943775] [Full Text: https://doi.org/10.1038/nature05050]
Ditton, H. J., Zimmer, J., Kamp, C., Rajpert-De Meyts, E., Vogt, P. H. The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum. Molec. Genet. 13: 2333-2341, 2004. [PubMed: 15294876] [Full Text: https://doi.org/10.1093/hmg/ddh240]
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]
Kretschmann, S., Herda, S., Bruns, H., Russ, J., van der Meijden, E. D., Schlotzer-Schrehardt, U., Griffioen, M., Na, I.-K., Mackensen, A., Kremer, A. N. Chaperone protein HSC70 regulates intercellular transfer of Y chromosome antigen DBY. J. Clin. Invest. 129: 2952-2962, 2019. [PubMed: 31205025] [Full Text: https://doi.org/10.1172/JCI123105]
Lahn, B. T., Page, D. C. Functional coherence of the human Y chromosome. Science 278: 675-680, 1997. [PubMed: 9381176] [Full Text: https://doi.org/10.1126/science.278.5338.675]
Rosinski, K. V., Fujii, N., Mito, J. K., Koo, K. K. W., Xuereb, S. M., Sala-Torra, O., Gibbs, J. S., Radich, J. P., Akatsuka, Y., Van den Eynde, B. J., Riddell, S. R., Warren, E. H. DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells. Blood 111: 4817-4826, 2008. [PubMed: 18299450] [Full Text: https://doi.org/10.1182/blood-2007-06-096313]
Scott, D., Addey, C., Ellis, P, James, E., Mitchell, M. J., Saut, N., Jurcevic, S., Simpson, E. Dendritic cells permit identification of genes encoding MHC class II-restricted epitopes of transplantation antigens. Immunity 12: 711-720, 2000. [PubMed: 10894170] [Full Text: https://doi.org/10.1016/s1074-7613(00)80221-6]
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]