TWENTY-FOUR GENES ARE UPREGULATED
IN PATIENTS WITH HYPOSPADIAS Karabulut R1, Turkyilmaz Z1, Sonmez K1, Kumas G2, Ergun SG2, Ergun MA2,*, Basaklar AC1 *Corresponding Author: Mehmet A. Ergun, M.D., Ph.D., Department of Medical Genetics, Gazi University
Faculty of Medicine, Besevler, Ankara, Turkey; Tel.: +90 312 2024637; Fax. +90 312 2024635; E-mail:
aliergun@gazi.edu.tr page: 39
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DISCUSSION
Hypospadias has multifactorial origins that involve
the actions of environmental factors with a
genetic background [8]. The previous microarray
studies indicated that, activating transcription factor
3 (ATF3), connective tissue growth factor (CTGF)
and cysteine-rich, angiogenic inducer 61 (CYR61)
genes were upregulated in hypospadias and all three
genes were also estrogen-responsive [8-10].
The ATF3 gene is upregulated in the skin of
patients with hypospadias compared to normal prepuce.
Also, ATF3 expression at the mRNA level in
fetal mouse tissues demonstrated that its mRNA is
expressed significantly more in genital tubercles
from fetal mice exposed in utero to estrogens than
in those of unexposed fetal mice [4,10]. This gene
has a role in suppression of cell cycling; therefore,
it had been hypothesized that its role in hypospadias
might be inhibition of cell growth in urethral
formation. ATF3 is upregulated in human and
mouse hypospadiac tissues compared with control
tissues, at both the mRNA and protein levels [8].
It has been suggested that ATF3 may play a role
in development of hypospadias as a result of exposure
to estrogenic compounds [11]. Sequence
variants of the ATF3 gene may be involved in the
genetic risk for hypospadias [12]. These genomic
variants of ATF3 have been reported to be present
in 10.0% of patients with hypospadias [13]. In
our study, we detected an upregulation of the ATF3
gene by 13-fold in hypospadias tissues with respect
to the controls.
The other genes that have been identified from
a human microarray analysis study were CTGF and
CYR61. These genes were both members of the cyclin
gene family and might have roles in matrix remodeling
through the activation of metalloproteinases
[8,10]. Our study only revealed an upregulation
of the CYR61 gene by 5.8-6.0-fold.
Among the other 22 upregulated genes, several
patterns of genes including apoptosis (FOS), apoptosis
and signalling (NR4A1), metabolism (PTGS2),
protein binding (RTN4), receptor activity (CD69),
signalling (DUSP1, SOCS3, NR4A2, EGR1, RGS1,
HBEGF, CD9), transcription (FOSB, JUN, JUNB,
IER2, ZFP36, KLF2, BTG2, HNRNPUL1), translation
(EIF4A1) and transporter activites (SLC25A25)
were also assessed (Table 1).
With regard to the top upregulated genes,
FOS and NR4A1, were shown to induce apoptosis
(Table 1). Such expression of the FOS gene has
been associated with apoptotic cell death, whereas
the NR4A1 gene has also been reported to induce
apoptosis [14,15]. These two apoptotic genes (FOS,
NR4A1) have not been reported before.
It has been reported that apoptosis may induce
external genitalia defects in fetal mouse [16]. The
events leading to hypospadias formation had also
been demonstrated to be associated with apoptotic
and proliferative events in dorsal urethral epithelia
and sinus cord [17]. However, Baskin et al. [18] indicated
that hypospadias resulted from an arrest in
urethral seam formation or seam remodeling but not
by an epithelial apoptosis. Thus, the apoptotic genes
need to be studied in a larger population.
In this study, we found a relation between hypospadias
and the previously reported ATF3 and
CYR61 genes. We also detected an upregulation of
22 genes in hypospadias patients that have not been
reported before. Further studies including GWAS
with expression studies in a larger patient group will
help us to identify the candidate gene(s) in the etiology
of hypospadias.
Declaration of Interest: This study was sponsored
by the Scientific Research Foundation of Gazi
University (01/2012-59). The authors report no conflicts
of interest. The authors alone are responsible
for the content and writing of this article.
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