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

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.



Number 26
Number 26 VOL. 26(2), 2023 All in one
Number 26
VOL. 26(2), 2023
Number 26
VOL. 26, 2023 Supplement
Number 26
VOL. 26(1), 2023
Number 25
VOL. 25(2), 2022
Number 25
VOL. 25 (1), 2022
Number 24
VOL. 24(2), 2021
Number 24
VOL. 24(1), 2021
Number 23
VOL. 23(2), 2020
Number 22
VOL. 22(2), 2019
Number 22
VOL. 22(1), 2019
Number 22
VOL. 22, 2019 Supplement
Number 21
VOL. 21(2), 2018
Number 21
VOL. 21 (1), 2018
Number 21
VOL. 21, 2018 Supplement
Number 20
VOL. 20 (2), 2017
Number 20
VOL. 20 (1), 2017
Number 19
VOL. 19 (2), 2016
Number 19
VOL. 19 (1), 2016
Number 18
VOL. 18 (2), 2015
Number 18
VOL. 18 (1), 2015
Number 17
VOL. 17 (2), 2014
Number 17
VOL. 17 (1), 2014
Number 16
VOL. 16 (2), 2013
Number 16
VOL. 16 (1), 2013
Number 15
VOL. 15 (2), 2012
Number 15
VOL. 15, 2012 Supplement
Number 15
Vol. 15 (1), 2012
Number 14
14 - Vol. 14 (2), 2011
Number 14
The 9th Balkan Congress of Medical Genetics
Number 14
14 - Vol. 14 (1), 2011
Number 13
Vol. 13 (2), 2010
Number 13
Vol.13 (1), 2010
Number 12
Vol.12 (2), 2009
Number 12
Vol.12 (1), 2009
Number 11
Vol.11 (2),2008
Number 11
Vol.11 (1),2008
Number 10
Vol.10 (2), 2007
Number 10
10 (1),2007
Number 9
1&2, 2006
Number 9
3&4, 2006
Number 8
1&2, 2005
Number 8
3&4, 2004
Number 7
1&2, 2004
Number 6
3&4, 2003
Number 6
1&2, 2003
Number 5
3&4, 2002
Number 5
1&2, 2002
Number 4
Vol.3 (4), 2000
Number 4
Vol.2 (4), 1999
Number 4
Vol.1 (4), 1998
Number 4
3&4, 2001
Number 4
1&2, 2001
Number 3
Vol.3 (3), 2000
Number 3
Vol.2 (3), 1999
Number 3
Vol.1 (3), 1998
Number 2
Vol.3(2), 2000
Number 2
Vol.1 (2), 1998
Number 2
Vol.2 (2), 1999
Number 1
Vol.3 (1), 2000
Number 1
Vol.2 (1), 1999
Number 1
Vol.1 (1), 1998

 

 


 About the journal ::: Editorial ::: Subscription ::: Information for authors ::: Contact
 Copyright © Balkan Journal of Medical Genetics 2006