Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias.
BACKGROUND
Hypospadias is a common inborn error of the genital development, whose complex etiology remains elusive. Defects of the androgen metabolism and activity have been found in a subset of boys with hypospadias. Moreover, the balance between androgens and estrogens seems to be important to the proper male genital development. Activating transcription factor 3 (ATF3), an estrogen responsive gene, has been reported to be expressed during sexual development and up-regulated in hypospadic genital skin. We investigated ATF3 as a candidate gene for hypospadias.


METHODS
Genotyping of eight-tagged single nucleotide polymorphisms (SNP)s was performed in 330 boys with hypospadias and in 380 healthy controls. Screening for mutations in ATF3 was conducted in a subset of boys with hypospadias. ATF3 expression was evaluated in the foreskin of boys with hypospadias and in healthy controls and in the human fetal genitalia by immunohistochemistry.


RESULTS
Three common SNPs, spanning a region of about 16 kb in intron 1 of ATF3, are associated with hypospadias. These SNPs are not linked and their effects are independent. The combination of the three risk SNPs yields the highest significance. Mutation screening identified the gene variant c536A>G in one patient and c817C>T in the 3'-UTR in two other patients. ATF3 expression was evidenced in the developing male urethra.


CONCLUSIONS
ATF3 gene variants influence the risk of hypospadias. Its hormonal responsiveness may underlie this risk effect. But also other ATF3-dependent biological aspects, such as cell survival and death, response to stress stimuli, or the control of epithelial-mesenchymal interactions, may be of importance.
Beleza-Meireles
Ana
A
Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Töhönen
Virpi
V
Söderhäll
Cilla
C
Schwentner
Christian
C
Radmayr
Christian
C
Kockum
Ingrid
I
Nordenskjöld
Agneta
A
D051700:Activating Transcription Factor 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005333:Fetus; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005836:Genitalia, Female / Q000502:physiology; D005837:Genitalia, Male / Q000002:abnormalities* / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D007150:Immunohistochemistry; D007438:Introns; D016015:Logistic Models; D008297:Male; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D020836:Protein Structure, Quaternary; D012307:Risk Factors
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3