Activating Transcription Factor 3: An Estrogen Responsive Gene in the Aetiology of Hypospadias
Abstract Purpose Hypospadias is a common malformation in boys and the complex aetiology remains elusive. Initially mainly androgen, but also estrogen imbalances are likely involved in the aetiology of hypospadias. ATF3, a hormone responsive gene, has been reported to be up-regulated during sexual development, as well as in hypospadic genital skin. We investigated ATF3 as a candidate gene for hypospadias. Material and Methods Genotyping of eight tagged SNPs was performed in 330 boys with hypospadias and in 380 healthy controls. In addition, screening for mutations in ATF3 was conducted in 102 boys with hypospadias. ATF3 expression in the foreskin of boys with hypospadias and in healthy controls, as well as in the human foetal genitalia, was analyzed by immunohistochemistry. Results Three common SNPs, spanning a region of about 16 kb in intron 1 of ATF3, are associated with hypospadias. Sequence analysis revealed the gene variant c536A > G (pArg90Gly) in one patient; and c817C > T in the 3'UTR in two other patients. These variants were not present in the 380 controls. ATF3 expression was observed in the developing male urethra, in the developing vagina and in the rectal region in both sexes; and in the pre-pubertal genital tissue. Conclusions Sequence variants in the ATF3 gene influence the risk to hypospadias. Its responsiveness to estrogen may underlie this risk effect. In addition, other ATF3 dependent biological aspects, such as cell survival and cell death, response to stress stimuli or the control of epithelial-mesenchymal interactions, may be of importance.