These findings suggest that the CXorf6 mutations cause hypospadias primarily because of testicular dysfunction and resultant compromised testosterone production around that period, and provide useful information for the molecular network involved in fetal testosterone production.
The SNPs in ESR2 and ATF3 were borderline associated with hypospadias [odds ratios 0.9 (95% confidence interval 0.7-1.0) and 1.2 (95% confidence interval 1.0-1.4), respectively] but in the opposite direction compared with earlier publications.
Mastermind-like domain containing 1/chromosome X open reading frame 6 mutation and activating transcription factor 3 variants have been shown to be associated with the incidence of isolated hypospadias.
ATF3 is involved in the TGF-beta epithelial-mesenchymal signaling pathway, and its involvement in hypospadias suggests that ATF3 plays a role in development of this anomaly as a result of exposure to estrogenic compounds.
Our results indicate that ATF3 is up-regulated in the penile skin tissues of boys with hypospadias, suggesting a role for this transcription factor in the development of this abnormality.
Mice mutant for Hoxa13 also exhibit changes in androgen receptor expression, providing a developmental link between Hoxa13-associated hypospadias and those produced by antagonists to androgen signaling.