Atlas of Genetics and Cytogenetics

in Oncology and Haematology

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Gene Section Review

TSPY1 (testis specific , Y-linked 1) Stephanie Schubert Hannover Medical School, Institute for Human Genetics, Hannover, Germany (SS)

Published in Atlas Database: June 2013 Online updated version : http://AtlasGeneticsOncology.org/Genes/TSPY1ID42718chYp11.html DOI: 10.4267/2042/52074 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract: Review on TSPY1, with data on DNA/RNA, on the protein encoded and where the is implicated.

array (Skaletsky et al., 2003). Especially this Identity ampliconic TSPY1 gene array on Yp11.2 is a hotspot Other names: CT78, DYS14, TSPY, pJA923 for intrachromosomal recombination likely by unequal HGNC (Hugo): TSPY1 sister chromatid exchange (Skaletsky et al., 2003) that leads to differences in copy number among men. It has Location: Yp11.2 to be mentioned that the TSPY nomenclature is far Local order: TSPY1 is a Y-chromosomal repetitive from being established right now. gene which is organized in clusters. The major TSPY1 Besides the TSPY1 and TSPY3 were also cluster is a constitutive part of the DYZ5-tandem array TSPY2, TSPY4, TSPY8 and TSPY10 genes and where each TSPY1 copy is surrounded by a single multiple TSPY pseudogenes (TSPYPn) annotated on DYZ5 20.4 kb repeat unit. This TSPY1 tandem array is Yp11.2 on the human Y (reference the largest and most homogeneous protein coding NC_00024.9). Controversially, TSPY1 was earlier tandem array that is known in the . designated as one out of the multiple TSPY genes Note within the TSPY tandem array (Bhowmick et al., DYS14 is located within the TSPY gene and pJA923 2007). was the first isolated TSPY-cDNA clone (Arnemann et Description al., 1991). The prototypic human TSPY gene is composed of six exons and five introns and a promoter region of yet DNA/RNA unknown length. Functional TSPY genes can differ in Note sequence within coding and promoter regions of up to Human TSPY was originally identified as the first Y- 1% (Vogel and Schmidtke, 1998). chromosomal gene, which expression was exclusively Transcription restricted to the testis (Arnemann et al., 1987). Besides the TSPY1 main transcript TSPY-L Nowadays it is known that TSPY is predominantly (NM_003308.3), which was originally named as expressed in the testes and to much lesser extent major TSPY (Schnieders et al., 1996) or type 1 TSPY expressed in the native prostate and the human brain transcript (Lau et al., 2003), eleven different transcript (Kido and Lau, 2005; Lau et al., 2003). isoforms that differ in sequence and in length were The organization of human TSPY on the human Y detected in the testis, and in prostatic and testicular chromosome as a heterogeneous repetitive gene family tumors (Zhang et al., 1992; Dechend et al., 2000; with varying copy number ranging from 9-101 among Schnieders et al., 1996; Lau et al., 2003; Li et al., individuals is unusual in the human genome 2007). One of these TSPY1 minor transcripts is the (Nickkholgh et al., 2010; Giachini et al., 2009; Shen et TSPY-S variant (NM_001197242.1) which uses an al., 2013). Besides a single separate functional TSPY alternative splice acceptor site 11 bp upstream of the gene (TSPY3) on Yp are most TSPY copies (TSPY1) native intron 5/exon 5 border of the main TSPY-L embedded in 20.4 kb repeat units of the DYZ5 tandem transcript (Zhang et al., 1992).

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TSPY gene and TSPY transcripts that were identified in human testes [T] (Schnieders et al., 1998, Dechend et al., 2000; Li et al., 2007), testicular seminoma [TC] (Li et al., 2007) and prostatic adenoma and benign prostatic hyperplasia [P] (Lau et al., 2003) tissues. Exons 1- 6 are highlighted as colored boxes and introns 1-5 are shown as grey bars. Small vertical grey bars are showing alternative splice donor and/or splice acceptor sites. 18bp insertion: in frame insertion of 18 nucleotides within exon 1, + combined splice patterns. This figure was originally modified published in Schubert and Schmidtke (2010).

TSPY-S is translated in a shortened distinct peptide paralogs and with SET and NAP-1 a highly-conserved (NP_001184171.1) of 294 amino acids with type B cyclin binding SET/NAP domain (amino acids frameshifted ORF at amino acid position 275 in residues 121-265 according to Li and Lau, 2008). comparison to TSPY-L. The TSPY-L transcript has a For human TSPY the translation elongation factor length of 1160 bp and encodes for a TSPY-L peptide of eEF1A1 has also been identified as binding partner of 308 amino acids (NP_003299.2). the SET/NAP domain in a yeast-two-hybrid screen Pseudogene (Kido and Lau, 2008). An interaction of TSPY with eEF1A1 and eEF1A2 was also shown by in vitro GST- Multiple annotated TSPY pseudogenes (TSPYPn) are pull down assays by Kido and Lau (2008). available on the human . These TSPY An in vitro binding of the SET/NAP domain of TSPY pseudogenes can show a nucleotide divergence in and the calcium/calmodulin-dependent serine protein coding and promoter regions of up to 10% (Vogel and kinase (CASK), which is among other things essential Schmidtke, 1998). for synapsis formation and memory, was also demonstrated in transfected COS7 cells (Kido et al., Protein 2011). Besides the cyclin B, eEF1A1 and CASK interactive Description SET/NAP domain is TSPY-L harbouring an N- Human TSPY1 encodes the TSPY1 protein. The main terminus of 120 and a C-terminus of 43 amino acids. protein is named TSPY-L and is composed of 308 Two putative homodimer forming α-helices ( α1, aa 52- amino acids (size 33 kDa). TSPY-L occurs mainly as a 95 and α2, aa 105-141) were predicted within the N- phosphoprotein with a predicted size of 38 kDa terminal region by in silico analysis (Kido and Lau, (Schnieders et al., 1996). TSPY is sharing with its X- 2008). It was further shown by co-immunprecipitation encoded homolog TSPYL2 (designated also as TSPX, of TSPY from transfected COS7 cells that TSPY can CDA1, DENTT or NP79), autosomal TSPY-like form homodimers, which is presumably mediated

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through the α-helices of its N-terminal region (Kido autosomal encoded paralogs TSPYL1, TSPYL3, and Lau, 2008). TSPYL4, TSPYL5, TSPYL6 members of this protein The N-terminal region of TSPY is also capable to bind family. Members of the SET/NAP-protein-family play to the androgen receptor (AR) AF-2 region (Akimoto et function in cell cycle regulation, transcription, al., 2010). For rat TSPY it was also shown that the N- translation, signal transduction, DNA replication and terminal region of rat TSPY is preferentially binding to chromatin condensation (Lau et al., 2009; Lau et al., core histones, although a much lower binding affinity 2011 and included references). for core histones was also observed for the acidic part - Ectopic expression of TSPY in transfected human of the SET/NAP domain of rat TSPY (Kido and Lau, HeLa and murine NIH3T3 cells stimulates cell growth 2006). by promoting the G2/M-phase transition of the cell Expression cycle (Oram et al., 2006). It was later shown in transiently transfected HeLa and HEK293 cells that this Human TSPY is mainly expressed in testicular germ effect is mediated by a direct interaction of the cells and weakly expressed in epithelial cells of the SET/NAP domain of TSPY with the activated cyclin prostate. However, some TSPY ESTs originated from B1/CDK complex. TSPY accelerates the G2/M-phase the medulla of human brains are also available in transition of host cells by stimulating the kinase activity databases (Kido and Lau, 2005). TSPY is expressed in of the activated cyclin B1/CDK complex (Li et al., gonocytes and prespermatogonia of the fetal testis and 2008). The co-localization of TSPY and cyclin B1 in in prespermatogonia of the neonatal testis (Honecker et spermatogonia and primary spermatocytes suggests a al., 2004). Within the adult testis are highest TSPY putative interaction of both during expression levels observed in spermatogonia and in spermatogonial renewal and during the prophase I of primary spermatocytes of the preleptotene to zygotene the first meiotic division (Lau et al., 2011). However, stage of the meiotic prophase I, while expression level the relevance of TSPY's ability to stimulate the kinase decreases gradually during meiosis form primary activity of an activated cyclin B1/cdk complex in spermatocytes of the pachytene stage to round transiently transfected human HEK293 cells to its in spermatids (Lau et al., 2011). vivo function within the testis is still unclear. Localisation - Kido and Lau (2008) have identified the eucaryotic TSPY is predominantly localized in the cytoplasm but elongation factor 1 alpha (eEF1A) in a yeast two- also to lesser extent present in the nucleus of male germ hybrid screen as interaction partner for human and rat cells and epithelial cells of the prostate. It is supposed TSPY. It was shown by in vitro GST pull down assays that the phosphorylation status of the CK2 that eEF1A1 and eEF1A2, which both are essential for phosphorylation site (T300) at the C-terminus of the elongation phase of protein translation, can bind to human TSPY is important for its nucleo-cytoplasmatic the SET/NAP domain of human TSPY. Kido and Lau shuttling (Krick et al., 2006). (2008) have also demonstrated that ectopic expression of TSPY in HEK293 cells enhances expression of a Function cotransfected luciferase reporter transcript. Whether Currently the biological role of TSPY within the testis this effect is mediated by a synergistically interaction and in the prostate are unknown but TSPY proposed of TSPY and eEF1A in reporter gene transcription and functions are diverse. Especially the conservation of translation is currently unknown. It is also still unclear functional TSPY genes in different mammalian whether TSPY could affect the expression of specific lineages indicates an important biological role of TSPY genes in spermatogonia and spermatocytes by in spermatogenesis. Expression studies of human TSPY interaction with eEF1A. The co-expression and co- within the human testis suggest that TSPY could act as localization of TSPY and eEF1A in spermatogonia and proliferation factor of testicular germ cells, such as spermatocytes makes an interaction of both proteins in gonocytes, prespermatogonia and spermatogonia in the the human testis not unlikely. The findings of the latter fetal, neonatal, pubertal and adult testis and could act as study suggest that TSPY and eEF1A could synergistic a catalyst in meiotic differentiation and division of exert progrowth functions on germ cells by promoting spermatocytes within the pubertal and adult testis gene expression. (Schnieders et al., 1996; Honecker et al., 2004; Lau et Other TSPY proposed functions are: al., 2011). These proposed functions are founded on the - It is also supposed that rat TSPY could affect following observations: spermatogenesis by acting as histone chaperone in - TSPY shares a highly conserved SET/NAP domain elongated spermatids during the maturation process with other members of a protein family that was when histones are replaced by basic protamines (Kido designated as TSPY/TSPY-like/SET/NAP (TTSN)- and Lau, 2006). It was shown by in vitro GST pull family (Schnieders et al., 1996; Vogel and Schmidtke, down assays that human TSPY and rTSPY can both 1998). Besides TSPY itself, are its X-encoded bind to the core histones H2A, H2B, H3 and H4, homologue TSPYL2, the oncogene SET (suppressor of respectively (Kido and Lau, 2006). The non variegation, enhancer of zeste and Trithorax), the overlapping expression pattern of human TSPY and neucleosome assembly protein-1 (NAP1) and the

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rTSPY in spermatids makes a function of human TSPY found no association between TSPY copy number and as histone chaperone in spermatids rather unlikely. the fertility status. Giacchini et al. (2009) showed that - TSPY is coexpressed with the androgen receptor in TSPY copy number and sperm count are positively testicular germ cell tumors (seminomas and correlated in infertile (n=154) and normozoospermic nonseminomas) and in prostatic tumors (Akimoto et al., (n=130) men, respectively, and observed a significantly 2010). TSPY can trap the androgen-bound androgen lower mean TSPY copy number in infertile men receptor in the cytoplasm of TSPY stably expressing compared to fertile controls. Interestingly, a significant NEC8-TSPY cells (a model nonseminoma cell line) difference in mean TSPY copy number among different and in TSPY endogenously expressing LNCaP cells, Y-haplogroups was also observed, which points to the thereby repressing AR mediated gene transcription susceptibility of the outcome of TSPY case-control (Akimoto et al., 2010). It is supposed that TSPY studies to population stratification bias. They estimated represses androgen dependent cell proliferation in a 1.5-fold increased risk of abnormal sperm parameters TGCTs, presumably by preventing AR nuclear in individuals with less than 33 TSPY copies. Recently, translocation. However TSPY is not coexpressed with the TSPY copy number was quantified by quantitative the human AR in testicular cells, which exclude such a PCR-analyses in a large case-control study in 2272 Han function in the native testis. Chinese, composed of 698 normozoospermic controls, - TSPY and CASK are coexpressed and co-localized in 704 men with AZFc-deletions and 870 spermatogenesis the brains of TSPY transgenic founder mice, carrying a impaired non-AZF deleted men (Shen et al., 2013). A human TSPY 12,5 kb genomic fragment, which significantly higher risk for spermatogenic failure were includes 7,1 kb TSPY promoter region, a 2,8 kb found for men with TSPY copy numbers ≤20 or ≥ 56 in structural TSPY gene and 2,6 kb 3'-region. Whether an comparison to individuals with moderate TSPY copies in vivo co-localization and interaction of both proteins ranging from 21-35. Sperm production in men with 21- exist in humans is currently unknown (Kido et al., 55 TSPY copies was significantly higher in comparison 2011). to men that harboured less than 21 or more than 55 TSPY copies. The latter study points also to a Homology modulating effect of the TSPY copy number to the Especially the SET/NAP domain of TSPY shares high spermatogenic status of AFZc-deleted men with gr/gr homology to other members of the TTSN-protein deletions (Shen et al., 2013). Especially males with family. gr/gr deletions and TSPY copy number less than 21 seems to have a high risk for spermatogenic failure and Mutations reduced sperm numbers. Further studies are indispensable to verify the putative effect of TSPY Note copy number on male idiopathic infertility, and Due to the multi-copy status of TSPY genes and the especially on the phenotypic expression of gr/gr presence of multiple TSPY pseudogenes on the Y deletion carriers. chromosome no disease associated mutations have been identified so far. Recently, multiple TSPY-variants Gonadoblastoma within the 5'-UTR, exon 1 and 3'-UTR have been Note identified in a screening approach of 72 infertile men TSPY is commonly regarded as the most reliable and 31 fertile men as controls (Svacinova et al., 2011). candidate gene for GBY, the elusive gonadoblastoma Out of these were 39 variants in exon 1 elusively locus on the human Y chromosome that fulfills a native restricted to the infertile cohort (Svacinova et al., function in the testis but predisposes the dysgenetic 2011). gonads of 46,XY-sex-revered and intersex individuals for the formation of a gonadoblastoma (Page, 1987; Implicated in Lau et al., 2011). TSPY abundant expression in germ cells of dysgenetic gonads of sex-reversed humans Male idiopathic infertility harbouring at least the GBY critical region (Cools et Note al., 2006) and in gonadoblastoma (Hildenbrand et al., Four different studies have proven a relation between 1999; Kersemaekers et al., 2005; Cools et al., 2006) the TSPY copy number and male idiopathic infertility depicts TSPY gonadoblastoma predisposing role. Apart with different outcome. Vodicka et al. (2007) assessed from this and TSPY strong expression in the the relative number of TSPY copies by RQF-PCR in an carcinoma-in situ of the testis (Schnieders et al., 1998; infertile group (84 cases) and in 40 controls, and found Li et al., 2007), in some seminomas (Hersmus et al., an association of higher number of TSPY copies with 2012) and some non-seminomatous impaired sperm production. germ cell tumors (Honecker et al., 2006), and some Nickkholgh et al. (2010) compared the absolute TSPY somatic tumors, such as prostatic tumors, melanoma copy numbers by quantitative PCR and Southern-Blot and hepatocellular carcinoma, exist no evidence for an analyses in selected cases of 100 men with idiopathic oncogenic role of TSPY in general. infertility versus 100 normozoospermic controls, and

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Vogel T, Boettger-Tong H, Nanda I, Dechend F, Agulnik AI, To be noted Bishop CE, Schmid M, Schmidtke J. A murine TSPY. Chromosome Res. 1998a Jan;6(1):35-40 Note Vogel T, Dittrich O, Mehraein Y, Dechend F, Schnieders F, TSPY genes have only been identified on the Y Schmidtke J. Murine and human TSPYL genes: novel of different placental mammals. So far members of the TSPY-SET-NAP1L1 family. Cytogenet Cell no homologue genes have been found in the genomes Genet. 1998b;81(3-4):265-70 of marsupials and monotremes (Delbridge et al., 2004). Vogel T, Schmidtke J. Structure and function of TSPY, the Y- While orthologue genes in other primates, in cattle and chromosome gene coding for the "testis-specific protein". in some rodents, such as the Syrian hamster and Mus Cytogenet Cell Genet. 1998;80(1-4):209-13 palthytrix are functionally conserved and organized in Hildenbrand R, Schröder W, Brude E, Schepler A, König R, multiple copies, a peculiar situation is observed in Stutte HJ, Arnemann J. Detection of TSPY protein in a some other muride rodents (Xue and Tyler-Smith, unilateral microscopic gonadoblastoma of a Turner mosaic 2011; Vogel et al., 1998b; Schubert et al., 2000; patient with a Y-derived marker chromosome. J Pathol. 1999 Dec;189(4):623-6 Karwacki et al., 2006). Tspy-ps degenerated as a single copy on the Y-chromosome in mice of the sugenus Dechend F, Williams G, Skawran B, Schubert S, Krawczak M, Tyler-Smith C, Schmidtke J. TSPY variants in six loci on the Mus and in the Mongolian gerbil while a unique still human Y chromosome. Cytogenet Cell Genet. 2000;91(1- functional gene copy is still retained in different 4):67-71 Apodemus species and in the rat (Vogel et al., 1998a; Schubert S, Dechend F, Skawran B, Kunze B, Winking H, Mazeyrat and Mitcheli, 1998; Schubert et al., 2000; Weile C, Römer I, Hemberger M, Fundele R, Sharma T, Karwacki et al., 2006). Schubert et al. (2003) generated Schmidtke J. Silencing of the Y-chromosomal gene tspy during a TSPY transgenic mouse line (NMRI- murine evolution. Mamm Genome. 2000 Apr;11(4):288-91 Tg(TSPY)9Jshm), carrying a human 8.2 kb genomic Lau YF, Lau HW, Kömüves LG. Expression pattern of a fragment consisting of 2.9 kb TSPY promoter region, gonadoblastoma candidate gene suggests a role of the Y 2.8 kb coding region and 2.5 bp of the TSPY 3'-region, chromosome in prostate cancer. Cytogenet Genome Res. in which the organization and expression of the human 2003;101(3-4):250-60 TSPY transgene follow the human pattern. In this line Schubert S, Skawran B, Dechend F, Nayernia K, Meinhardt A, approximately 50 copies of the human TSPY transgene Nanda I, Schmid M, Engel W, Schmidtke J. Generation and characterization of a transgenic mouse with a functional human are inserted on the mouse Y chromosome. TSPY TSPY. Biol Reprod. 2003 Sep;69(3):968-75 transgenic B6;NMRI-Ki W-v/Kit W-v mice on a mixed NMRI/C57BL/6J genetic background are able to Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T, partially rescue spermatogenesis and fertility of Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G, W-v homozygous Kit -mutant males, thereby pointing to a Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S, role of human TSPY in early fetal and adult germ cell Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen development (Schöner et al., 2010). C, Ozersky P, Pepin K, Rock S, Rohlfing T, Scott K, Schultz B, Strong C, Tin-Wollam A, Yang SP, Waterston RH, Wilson RK, Rozen S, Page DC. The male-specific region of the human Y References chromosome is a mosaic of discrete sequence classes. Nature. 2003 Jun 19;423(6942):825-37 Arnemann J, Epplen JT, Cooke HJ, Sauermann U, Engel W, Schmidtke J. A human Y-chromosomal DNA sequence Delbridge ML, Longepied G, Depetris D, Mattei MG, Disteche expressed in testicular tissue. Nucleic Acids Res. 1987 Nov CM, Marshall Graves JA, Mitchell MJ. TSPY, the candidate 11;15(21):8713-24 gonadoblastoma gene on the human Y chromosome, has a widely expressed homologue on the X - implications for Y Page DC. Hypothesis: a Y-chromosomal gene causes chromosome evolution. Chromosome Res. 2004;12(4):345-56 gonadoblastoma in dysgenetic gonads. Development. 1987;101 Suppl:151-5 Honecker F, Stoop H, de Krijger RR, Chris Lau YF, Bokemeyer C, Looijenga LH. Pathobiological implications of the expression Arnemann J, Jakubiczka S, Thüring S, Schmidtke J. Cloning of markers of testicular carcinoma in situ by fetal germ cells. J and sequence analysis of a human Y-chromosome-derived, Pathol. 2004 Jul;203(3):849-57 testicular cDNA, TSPY. Genomics. 1991 Sep;11(1):108-14 Kersemaekers AM, Honecker F, Stoop H, Cools M, Molier M, Zhang JS, Yang-Feng TL, Muller U, Mohandas TK, de Jong Wolffenbuttel K, Bokemeyer C, Li Y, Lau YF, Oosterhuis JW, PJ, Lau YF. Molecular isolation and characterization of an Looijenga LH. Identification of germ cells at risk for neoplastic expressed gene from the human Y chromosome. Hum Mol transformation in gonadoblastoma: an immunohistochemical Genet. 1992 Dec;1(9):717-26 study for OCT3/4 and TSPY. Hum Pathol. 2005 May;36(5):512-21 Schnieders F, Dörk T, Arnemann J, Vogel T, Werner M, Schmidtke J. Testis-specific protein, Y-encoded (TSPY) Kido T, Lau YF. A Cre gene directed by a human TSPY expression in testicular tissues. Hum Mol Genet. 1996 promoter is specific for germ cells and neurons. Genesis. 2005 Aug;42(4):263-75 Nov;5(11):1801-7 Cools M, Stoop H, Kersemaekers AM, Drop SL, Wolffenbuttel Mazeyrat S, Mitchell MJ. Rodent Y chromosome TSPY gene is KP, Bourguignon JP, Slowikowska-Hilczer J, Kula K, Faradz functional in rat and non-functional in mouse. Hum Mol Genet. SM, Oosterhuis JW, Looijenga LH. Gonadoblastoma arising in 1998 Mar;7(3):557-62 undifferentiated gonadal tissue within dysgenetic gonads. J Clin Endocrinol Metab. 2006 Jun;91(6):2404-13

Atlas Genet Cytogenet Oncol Haematol. 2014; 18(1) 36 TSPY1 (testis specific protein, Y-linked 1) Schubert S

Honecker F, Stoop H, Mayer F, Bokemeyer C, Castrillon DH, androgen receptor in androgen-dependent testicular germ-cell Lau YF, Looijenga LH, Oosterhuis JW. Germ cell lineage tumors. Proc Natl Acad Sci U S A. 2010 Nov differentiation in non-seminomatous germ cell tumours. J 16;107(46):19891-6 Pathol. 2006 Feb;208(3):395-400 Nickkholgh B, Noordam MJ, Hovingh SE, van Pelt AM, van der Karwacki V, Kovac J, Mauceri G, Backhaus A, Föhse L, Veen F, Repping S. Y chromosome TSPY copy numbers and Schmidtke J, Schubert S. Tspy is nonfunctional in the semen quality. Fertil Steril. 2010 Oct;94(5):1744-7 Mongolian gerbil but functional in the Syrian hamster. Genomics. 2006 Jul;88(1):65-73 Schöner A, Adham I, Mauceri G, Marohn B, Vaske B, Schmidtke J, Schubert S. Partial rescue of the KIT-deficient Kido T, Lau YF. The rat Tspy is preferentially expressed in testicular phenotype in KitW-v/KitW-v Tg(TSPY) mice. Biol elongated spermatids and interacts with the core histones. Reprod. 2010 Jul;83(1):20-6 Biochem Biophys Res Commun. 2006 Nov 10;350(1):56-67 Schubert S, Schmidtke J.. Transgenic mouse studies to Krick R, Aschrafi A, Hasgün D, Arnemann J. CK2-dependent understand the regulation, expression and function of the C-terminal phosphorylation at T300 directs the nuclear testis-specific protein Y-encoded (TSPY) gene. Genes. transport of TSPY protein. Biochem Biophys Res Commun. 2010;1(2):244-262. 2006 Mar 10;341(2):343-50 Kido T, Schubert S, Schmidtke J, Chris Lau YF.. Expression of Oram SW, Liu XX, Lee TL, Chan WY, Lau YF. TSPY the human TSPY gene in the brains of transgenic mice potentiates cell proliferation and tumorigenesis by promoting suggests a potential role of this Y chromosome gene in neural cell cycle progression in HeLa and NIH3T3 cells. BMC Cancer. functions. J Genet Genomics. 2011 May 20;38(5):181-91. doi: 2006 Jun 9;6:154 10.1016/j.jgg.2011.04.002. Epub 2011 Apr 15. Bhowmick BK, Satta Y, Takahata N. The origin and evolution Lau YF, Li Y, Kido T.. Role of the Y-located putative of human ampliconic gene families and ampliconic structure. gonadoblastoma gene in human spermatogenesis. Syst Biol Genome Res. 2007 Apr;17(4):441-50 Reprod Med. 2011 Feb;57(1-2):27-34. doi: 10.3109/19396368.2010.499157. Epub 2011 Jan 5. Li Y, Tabatabai ZL, Lee TL, Hatakeyama S, Ohyama C, Chan WY, Looijenga LH, Lau YF. The Y-encoded TSPY protein: a Svacinova V, Vodicka R, Vrtel R, Godava M, Kvapilova M, significant marker potentially plays a role in the pathogenesis Krejcirikova E, Dusek L, Bortlicek Z, Santavy J.. Sequence of testicular germ cell tumors. Hum Pathol. 2007 recombination in exon 1 of the TSPY gene in men with Oct;38(10):1470-81 impaired fertility. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2011 Sep;155(3):287-98. doi: Vodicka R, Vrtel R, Dusek L, Singh AR, Krizova K, Svacinova 10.5507/bp.2011.034. V, Horinova V, Dostal J, Oborna I, Brezinova J, Sobek A, Santavy J. TSPY gene copy number as a potential new risk Xue Y and Tyler-Smith C.. An Exceptional Gene: Evolution of factor for male infertility. Reprod Biomed Online. 2007 the TSPY Gene Family in Humans and Other Great Apes. May;14(5):579-87 Genes. 2011;2(1):36-47 Kido T, Lau YF. The human Y-encoded testis-specific protein Hersmus R, Stoop H, van de Geijn GJ, Eini R, Biermann K, interacts functionally with eukaryotic translation elongation Oosterhuis JW, Dhooge C, Schneider DT, Meijssen IC, Dinjens factor eEF1A, a putative oncoprotein. Int J Cancer. 2008 Oct WN, Dubbink HJ, Drop SL, Looijenga LH.. Prevalence of c-KIT 1;123(7):1573-85 mutations in gonadoblastoma and dysgerminomas of patients with disorders of sex development (DSD) and ovarian Li Y, Lau YF. TSPY and its X-encoded homologue interact with dysgerminomas. PLoS One. 2012;7(8):e43952. doi: cyclin B but exert contrasting functions on cyclin-dependent 10.1371/journal.pone.0043952. Epub 2012 Aug 28. kinase 1 activities. Oncogene. 2008 Oct 16;27(47):6141-50 Shen Y, Yan Y, Liu Y, Zhang S, Yang D, Zhang P, Li L, Wang Giachini C, Nuti F, Turner DJ, Laface I, Xue Y, Daguin F, Forti Y, Ma Y, Tao D, Yang Y.. A significant effect of the TSPY1 G, Tyler-Smith C, Krausz C. TSPY1 copy number variation copy number on spermatogenesis efficiency and the influences spermatogenesis and shows differences among Y phenotypic expression of the gr/gr deletion. Hum Mol Genet. lineages. J Clin Endocrinol Metab. 2009 Oct;94(10):4016-22 2013 Apr 15;22(8):1679-95. doi: 10.1093/hmg/ddt004. Epub Lau YF, Li Y, Kido T. Gonadoblastoma locus and the TSPY 2013 Jan 10. gene on the human Y chromosome. Birth Defects Res C Embryo Today. 2009 Mar;87(1):114-22 This article should be referenced as such: Akimoto C, Ueda T, Inoue K, Yamaoka I, Sakari M, Obara W, Schubert S. TSPY1 (testis specific protein, Y-linked 1). Atlas Fujioka T, Nagahara A, Nonomura N, Tsutsumi S, Aburatani H, Genet Cytogenet Oncol Haematol. 2014; 18(1):32-37. Miki T, Matsumoto T, Kitagawa H, Kato S. Testis-specific protein on Y chromosome (TSPY) represses the activity of the

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