Download Gene Section TSPY1 (testis specific protein, Y-linked 1) in Oncology and Haematology

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Gene Section
Review
TSPY1 (testis specific protein, 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 gene is implicated.
array (Skaletsky et al., 2003). Especially this
ampliconic TSPY1 gene array on Yp11.2 is a hotspot
for intrachromosomal recombination likely by unequal
sister chromatid exchange (Skaletsky et al., 2003) that
leads to differences in copy number among men. It has
to be mentioned that the TSPY nomenclature is far
from being established right now.
Besides the TSPY1 and TSPY3 genes were also
TSPY2, TSPY4, TSPY8 and TSPY10 genes and
multiple TSPY pseudogenes (TSPYPn) annotated on
Yp11.2 on the human Y chromosome (reference
NC_00024.9). Controversially, TSPY1 was earlier
designated as one out of the multiple TSPY genes
within the TSPY tandem array (Bhowmick et al.,
2007).
Identity
Other names: CT78, DYS14, TSPY, pJA923
HGNC (Hugo): TSPY1
Location: Yp11.2
Local order: TSPY1 is a Y-chromosomal repetitive
gene which is organized in clusters. The major TSPY1
cluster is a constitutive part of the DYZ5-tandem array
where each TSPY1 copy is surrounded by a single
DYZ5 20.4 kb repeat unit. This TSPY1 tandem array is
the largest and most homogeneous protein coding
tandem array that is known in the human genome.
Note
DYS14 is located within the TSPY gene and pJA923
was the first isolated TSPY-cDNA clone (Arnemann et
al., 1991).
Description
The prototypic human TSPY gene is composed of six
exons and five introns and a promoter region of yet
unknown length. Functional TSPY genes can differ in
sequence within coding and promoter regions of up to
1% (Vogel and Schmidtke, 1998).
DNA/RNA
Note
Human TSPY was originally identified as the first Ychromosomal gene, which expression was exclusively
restricted to the testis (Arnemann et al., 1987).
Nowadays it is known that TSPY is predominantly
expressed in the testes and to much lesser extent
expressed in the native prostate and the human brain
(Kido and Lau, 2005; Lau et al., 2003).
The organization of human TSPY on the human Y
chromosome as a heterogeneous repetitive gene family
with varying copy number ranging from 9-101 among
individuals is unusual in the human genome
(Nickkholgh et al., 2010; Giachini et al., 2009; Shen et
al., 2013). Besides a single separate functional TSPY
gene (TSPY3) on Yp are most TSPY copies (TSPY1)
embedded in 20.4 kb repeat units of the DYZ5 tandem
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(1)
Transcription
Besides the TSPY1 main transcript TSPY-L
(NM_003308.3), which was originally named as
TSPYmajor (Schnieders et al., 1996) or type 1 TSPY
transcript (Lau et al., 2003), eleven different transcript
isoforms that differ in sequence and in length were
detected in the testis, and in prostatic and testicular
tumors (Zhang et al., 1992; Dechend et al., 2000;
Schnieders et al., 1996; Lau et al., 2003; Li et al.,
2007). One of these TSPY1 minor transcripts is the
TSPY-S variant (NM_001197242.1) which uses an
alternative splice acceptor site 11 bp upstream of the
native intron 5/exon 5 border of the main TSPY-L
transcript (Zhang et al., 1992).
32
TSPY1 (testis specific protein, Y-linked 1)
Schubert S
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 16 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
(NP_001184171.1) of 294 amino acids with
frameshifted ORF at amino acid position 275 in
comparison to TSPY-L. The TSPY-L transcript has a
length of 1160 bp and encodes for a TSPY-L peptide of
308 amino acids (NP_003299.2).
paralogs and with SET and NAP-1 a highly-conserved
type B cyclin binding SET/NAP domain (amino acids
residues 121-265 according to Li and Lau, 2008).
For human TSPY the translation elongation factor
eEF1A1 has also been identified as binding partner of
the SET/NAP domain in a yeast-two-hybrid screen
(Kido and Lau, 2008). An interaction of TSPY with
eEF1A1 and eEF1A2 was also shown by in vitro GSTpull down assays by Kido and Lau (2008).
An in vitro binding of the SET/NAP domain of TSPY
and the calcium/calmodulin-dependent serine protein
kinase (CASK), which is among other things essential
for synapsis formation and memory, was also
demonstrated in transfected COS7 cells (Kido et al.,
2011).
Besides the cyclin B, eEF1A1 and CASK interactive
SET/NAP domain is TSPY-L harbouring an Nterminus of 120 and a C-terminus of 43 amino acids.
Two putative homodimer forming α-helices (α1, aa 5295 and α2, aa 105-141) were predicted within the Nterminal region by in silico analysis (Kido and Lau,
2008). It was further shown by co-immunprecipitation
of TSPY from transfected COS7 cells that TSPY can
form homodimers, which is presumably mediated
Pseudogene
Multiple annotated TSPY pseudogenes (TSPYPn) are
available on the human Y chromosome. These TSPY
pseudogenes can show a nucleotide divergence in
coding and promoter regions of up to 10% (Vogel and
Schmidtke, 1998).
Protein
Description
Human TSPY1 encodes the TSPY1 protein. The main
protein is named TSPY-L and is composed of 308
amino acids (size 33 kDa). TSPY-L occurs mainly as a
phosphoprotein with a predicted size of 38 kDa
(Schnieders et al., 1996). TSPY is sharing with its Xencoded homolog TSPYL2 (designated also as TSPX,
CDA1, DENTT or NP79), autosomal TSPY-like
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(1)
33
TSPY1 (testis specific protein, Y-linked 1)
Schubert S
through the α-helices of its N-terminal region (Kido
and Lau, 2008).
The N-terminal region of TSPY is also capable to bind
to the androgen receptor (AR) AF-2 region (Akimoto et
al., 2010). For rat TSPY it was also shown that the Nterminal region of rat TSPY is preferentially binding to
core histones, although a much lower binding affinity
for core histones was also observed for the acidic part
of the SET/NAP domain of rat TSPY (Kido and Lau,
2006).
autosomal encoded paralogs TSPYL1, TSPYL3,
TSPYL4, TSPYL5, TSPYL6 members of this protein
family. Members of the SET/NAP-protein-family play
function in cell cycle regulation, transcription,
translation, signal transduction, DNA replication and
chromatin condensation (Lau et al., 2009; Lau et al.,
2011 and included references).
- Ectopic expression of TSPY in transfected human
HeLa and murine NIH3T3 cells stimulates cell growth
by promoting the G2/M-phase transition of the cell
cycle (Oram et al., 2006). It was later shown in
transiently transfected HeLa and HEK293 cells that this
effect is mediated by a direct interaction of the
SET/NAP domain of TSPY with the activated cyclin
B1/CDK complex. TSPY accelerates the G2/M-phase
transition of host cells by stimulating the kinase activity
of the activated cyclin B1/CDK complex (Li et al.,
2008). The co-localization of TSPY and cyclin B1 in
spermatogonia and primary spermatocytes suggests a
putative interaction of both proteins during
spermatogonial renewal and during the prophase I of
the first meiotic division (Lau et al., 2011). However,
the relevance of TSPY's ability to stimulate the kinase
activity of an activated cyclin B1/cdk complex in
transiently transfected human HEK293 cells to its in
vivo function within the testis is still unclear.
- Kido and Lau (2008) have identified the eucaryotic
elongation factor 1 alpha (eEF1A) in a yeast twohybrid screen as interaction partner for human and rat
TSPY. It was shown by in vitro GST pull down assays
that eEF1A1 and eEF1A2, which both are essential for
the elongation phase of protein translation, can bind to
the SET/NAP domain of human TSPY. Kido and Lau
(2008) have also demonstrated that ectopic expression
of TSPY in HEK293 cells enhances expression of a
cotransfected luciferase reporter transcript. Whether
this effect is mediated by a synergistically interaction
of TSPY and eEF1A in reporter gene transcription and
translation is currently unknown. It is also still unclear
whether TSPY could affect the expression of specific
genes in spermatogonia and spermatocytes by
interaction with eEF1A. The co-expression and colocalization of TSPY and eEF1A in spermatogonia and
spermatocytes makes an interaction of both proteins in
the human testis not unlikely. The findings of the latter
study suggest that TSPY and eEF1A could synergistic
exert progrowth functions on germ cells by promoting
gene expression.
Other TSPY proposed functions are:
- It is also supposed that rat TSPY could affect
spermatogenesis by acting as histone chaperone in
elongated spermatids during the maturation process
when histones are replaced by basic protamines (Kido
and Lau, 2006). It was shown by in vitro GST pull
down assays that human TSPY and rTSPY can both
bind to the core histones H2A, H2B, H3 and H4,
respectively (Kido and Lau, 2006). The non
overlapping expression pattern of human TSPY and
Expression
Human TSPY is mainly expressed in testicular germ
cells and weakly expressed in epithelial cells of the
prostate. However, some TSPY ESTs originated from
the medulla of human brains are also available in
databases (Kido and Lau, 2005). TSPY is expressed in
gonocytes and prespermatogonia of the fetal testis and
in prespermatogonia of the neonatal testis (Honecker et
al., 2004). Within the adult testis are highest TSPY
expression levels observed in spermatogonia and in
primary spermatocytes of the preleptotene to zygotene
stage of the meiotic prophase I, while expression level
decreases gradually during meiosis form primary
spermatocytes of the pachytene stage to round
spermatids (Lau et al., 2011).
Localisation
TSPY is predominantly localized in the cytoplasm but
also to lesser extent present in the nucleus of male germ
cells and epithelial cells of the prostate. It is supposed
that the phosphorylation status of the CK2
phosphorylation site (T300) at the C-terminus of
human TSPY is important for its nucleo-cytoplasmatic
shuttling (Krick et al., 2006).
Function
Currently the biological role of TSPY within the testis
and in the prostate are unknown but TSPY proposed
functions are diverse. Especially the conservation of
functional TSPY genes in different mammalian
lineages indicates an important biological role of TSPY
in spermatogenesis. Expression studies of human TSPY
within the human testis suggest that TSPY could act as
proliferation factor of testicular germ cells, such as
gonocytes, prespermatogonia and spermatogonia in the
fetal, neonatal, pubertal and adult testis and could act as
a catalyst in meiotic differentiation and division of
spermatocytes within the pubertal and adult testis
(Schnieders et al., 1996; Honecker et al., 2004; Lau et
al., 2011). These proposed functions are founded on the
following observations:
- TSPY shares a highly conserved SET/NAP domain
with other members of a protein family that was
designated as TSPY/TSPY-like/SET/NAP (TTSN)family (Schnieders et al., 1996; Vogel and Schmidtke,
1998). Besides TSPY itself, are its X-encoded
homologue TSPYL2, the oncogene SET (suppressor of
variegation, enhancer of zeste and Trithorax), the
neucleosome assembly protein-1 (NAP1) and the
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(1)
34
TSPY1 (testis specific protein, Y-linked 1)
Schubert S
found no association between TSPY copy number and
the fertility status. Giacchini et al. (2009) showed that
TSPY copy number and sperm count are positively
correlated in infertile (n=154) and normozoospermic
(n=130) men, respectively, and observed a significantly
lower mean TSPY copy number in infertile men
compared to fertile controls. Interestingly, a significant
difference in mean TSPY copy number among different
Y-haplogroups was also observed, which points to the
susceptibility of the outcome of TSPY case-control
studies to population stratification bias. They estimated
a 1.5-fold increased risk of abnormal sperm parameters
in individuals with less than 33 TSPY copies. Recently,
the TSPY copy number was quantified by quantitative
PCR-analyses in a large case-control study in 2272 Han
Chinese, composed of 698 normozoospermic controls,
704 men with AZFc-deletions and 870 spermatogenesis
impaired non-AZF deleted men (Shen et al., 2013). A
significantly higher risk for spermatogenic failure were
found for men with TSPY copy numbers ≤20 or ≥ 56 in
comparison to individuals with moderate TSPY copies
ranging from 21-35. Sperm production in men with 2155 TSPY copies was significantly higher in comparison
to men that harboured less than 21 or more than 55
TSPY copies. The latter study points also to a
modulating effect of the TSPY copy number to the
spermatogenic status of AFZc-deleted men with gr/gr
deletions (Shen et al., 2013). Especially males with
gr/gr deletions and TSPY copy number less than 21
seems to have a high risk for spermatogenic failure and
reduced sperm numbers. Further studies are
indispensable to verify the putative effect of TSPY
copy number on male idiopathic infertility, and
especially on the phenotypic expression of gr/gr
deletion carriers.
rTSPY in spermatids makes a function of human TSPY
as histone chaperone in spermatids rather unlikely.
- TSPY is coexpressed with the androgen receptor in
testicular germ cell tumors (seminomas and
nonseminomas) and in prostatic tumors (Akimoto et al.,
2010). TSPY can trap the androgen-bound androgen
receptor in the cytoplasm of TSPY stably expressing
NEC8-TSPY cells (a model nonseminoma cell line)
and in TSPY endogenously expressing LNCaP cells,
thereby repressing AR mediated gene transcription
(Akimoto et al., 2010). It is supposed that TSPY
represses androgen dependent cell proliferation in
TGCTs, presumably by preventing AR nuclear
translocation. However TSPY is not coexpressed with
the human AR in testicular cells, which exclude such a
function in the native testis.
- TSPY and CASK are coexpressed and co-localized in
the brains of TSPY transgenic founder mice, carrying a
human TSPY 12,5 kb genomic fragment, which
includes 7,1 kb TSPY promoter region, a 2,8 kb
structural TSPY gene and 2,6 kb 3'-region. Whether an
in vivo co-localization and interaction of both proteins
exist in humans is currently unknown (Kido et al.,
2011).
Homology
Especially the SET/NAP domain of TSPY shares high
homology to other members of the TTSN-protein
family.
Mutations
Note
Due to the multi-copy status of TSPY genes and the
presence of multiple TSPY pseudogenes on the Y
chromosome no disease associated mutations have been
identified so far. Recently, multiple TSPY-variants
within the 5'-UTR, exon 1 and 3'-UTR have been
identified in a screening approach of 72 infertile men
and 31 fertile men as controls (Svacinova et al., 2011).
Out of these were 39 variants in exon 1 elusively
restricted to the infertile cohort (Svacinova et al.,
2011).
Gonadoblastoma
Note
TSPY is commonly regarded as the most reliable
candidate gene for GBY, the elusive gonadoblastoma
locus on the human Y chromosome that fulfills a native
function in the testis but predisposes the dysgenetic
gonads of 46,XY-sex-revered and intersex individuals
for the formation of a gonadoblastoma (Page, 1987;
Lau et al., 2011). TSPY abundant expression in germ
cells of dysgenetic gonads of sex-reversed humans
harbouring at least the GBY critical region (Cools et
al., 2006) and in gonadoblastoma (Hildenbrand et al.,
1999; Kersemaekers et al., 2005; Cools et al., 2006)
depicts TSPY gonadoblastoma predisposing role. Apart
from this and TSPY strong expression in the
carcinoma-in situ of the testis (Schnieders et al., 1998;
Li et al., 2007), in some seminomas (Hersmus et al.,
2012) and some non-seminomatous
germ cell tumors (Honecker et al., 2006), and some
somatic tumors, such as prostatic tumors, melanoma
and hepatocellular carcinoma, exist no evidence for an
oncogenic role of TSPY in general.
Implicated in
Male idiopathic infertility
Note
Four different studies have proven a relation between
the TSPY copy number and male idiopathic infertility
with different outcome. Vodicka et al. (2007) assessed
the relative number of TSPY copies by RQF-PCR in an
infertile group (84 cases) and in 40 controls, and found
an association of higher number of TSPY copies with
impaired sperm production.
Nickkholgh et al. (2010) compared the absolute TSPY
copy numbers by quantitative PCR and Southern-Blot
analyses in selected cases of 100 men with idiopathic
infertility versus 100 normozoospermic controls, and
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(1)
35
TSPY1 (testis specific protein, Y-linked 1)
Schubert S
Vogel T, Boettger-Tong H, Nanda I, Dechend F, Agulnik AI,
Bishop CE, Schmid M, Schmidtke J. A murine TSPY.
Chromosome Res. 1998a Jan;6(1):35-40
To be noted
Note
TSPY genes have only been identified on the Y
chromosomes of different placental mammals. So far
no homologue genes have been found in the genomes
of marsupials and monotremes (Delbridge et al., 2004).
While orthologue genes in other primates, in cattle and
in some rodents, such as the Syrian hamster and Mus
palthytrix are functionally conserved and organized in
multiple copies, a peculiar situation is observed in
some other muride rodents (Xue and Tyler-Smith,
2011; Vogel et al., 1998b; Schubert et al., 2000;
Karwacki et al., 2006). Tspy-ps degenerated as a single
copy on the Y-chromosome in mice of the sugenus
Mus and in the Mongolian gerbil while a unique still
functional gene copy is still retained in different
Apodemus species and in the rat (Vogel et al., 1998a;
Mazeyrat and Mitcheli, 1998; Schubert et al., 2000;
Karwacki et al., 2006). Schubert et al. (2003) generated
a
TSPY
transgenic
mouse
line
(NMRITg(TSPY)9Jshm), carrying a human 8.2 kb genomic
fragment consisting of 2.9 kb TSPY promoter region,
2.8 kb coding region and 2.5 bp of the TSPY 3'-region,
in which the organization and expression of the human
TSPY transgene follow the human pattern. In this line
approximately 50 copies of the human TSPY transgene
are inserted on the mouse Y chromosome. TSPY
transgenic B6;NMRI-KiW-v/KitW-v mice on a mixed
NMRI/C57BL/6J genetic background are able to
partially rescue spermatogenesis and fertility of
homozygous KitW-v-mutant males, thereby pointing to a
role of human TSPY in early fetal and adult germ cell
development (Schöner et al., 2010).
Vogel T, Dittrich O, Mehraein Y, Dechend F, Schnieders F,
Schmidtke J. Murine and human TSPYL genes: novel
members of the TSPY-SET-NAP1L1 family. Cytogenet Cell
Genet. 1998b;81(3-4):265-70
Vogel T, Schmidtke J. Structure and function of TSPY, the Ychromosome gene coding for the "testis-specific protein".
Cytogenet Cell Genet. 1998;80(1-4):209-13
Hildenbrand R, Schröder W, Brude E, Schepler A, König R,
Stutte HJ, Arnemann J. Detection of TSPY protein in a
unilateral microscopic gonadoblastoma of a Turner mosaic
patient with a Y-derived marker chromosome. J Pathol. 1999
Dec;189(4):623-6
Dechend F, Williams G, Skawran B, Schubert S, Krawczak M,
Tyler-Smith C, Schmidtke J. TSPY variants in six loci on the
human Y chromosome. Cytogenet Cell Genet. 2000;91(14):67-71
Schubert S, Dechend F, Skawran B, Kunze B, Winking H,
Weile C, Römer I, Hemberger M, Fundele R, Sharma T,
Schmidtke J. Silencing of the Y-chromosomal gene tspy during
murine evolution. Mamm Genome. 2000 Apr;11(4):288-91
Lau YF, Lau HW, Kömüves LG. Expression pattern of a
gonadoblastoma candidate gene suggests a role of the Y
chromosome in prostate cancer. Cytogenet Genome Res.
2003;101(3-4):250-60
Schubert S, Skawran B, Dechend F, Nayernia K, Meinhardt A,
Nanda I, Schmid M, Engel W, Schmidtke J. Generation and
characterization of a transgenic mouse with a functional human
TSPY. Biol Reprod. 2003 Sep;69(3):968-75
Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS,
Hillier L, Brown LG, Repping S, Pyntikova T, Ali J, Bieri T,
Chinwalla A, Delehaunty A, Delehaunty K, Du H, Fewell G,
Fulton L, Fulton R, Graves T, Hou SF, Latrielle P, Leonard S,
Mardis E, Maupin R, McPherson J, Miner T, Nash W, Nguyen
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
chromosome is a mosaic of discrete sequence classes.
Nature. 2003 Jun 19;423(6942):825-37
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