title: Evidence for epigenetic abnormalities of the androgen receptor gene in foreskin from children with hypospadias.
abstract: BACKGROUND
  Hypospadias is a malformation of the penis due to an incomplete development of the male urethra, the exact etiology of which in the majority of cases remains unknown.
  
  
  OBJECTIVE
  The objective of the study was to assess whether defects of the androgen receptor (AR) gene (CAG repeats and methylation pattern) and DNA methyltransferases (DNMT) family are present in hypospadic patients.
  
  
  METHODS
  CAG repeats length, methylation status, and expression of the AR gene were analyzed. The DNMT family was studied at the protein level and the DNMT3A sequenced.
  
  
  METHODS
  The study was performed at a pediatric endocrinology referral clinic.
  
  
  METHODS
  Twenty boys with isolated glandular hypospadias and 20 age-matched control children undergoing a surgical procedure for circumcision were studied.
  
  
  METHODS
  CAG repeats length and AR methylation pattern in PBLs and foreskin tissue, DNMT expression and sequencing in patients and controls, and in vitro studies in cultured fibroblasts were measured.
  
  
  RESULTS
  AR gene methylation in foreskin tissues from patients with hypospadias was higher than in normal children. AR expression in foreskin tissue of hypospadic patients was lower than in controls, whereas the DNMT3A protein level was significantly higher in patients than controls. In cultured fibroblasts, both dihydrotestosterone and testosterone significantly reduced AR gene methylation and DNMT3A expression in a dose-dependent fashion and increased AR expression.
  
  
  CONCLUSIONS
  The AR gene in target tissues from patients with hypospadias is more methylated than in control children, resulting in a decreased expression of the AR. The mechanism underlying the modulation of the AR gene expression seems to be mediated by DNMT3A. This epigenetic alteration of the AR gene might be involved in the pathogenesis of hypospadias.
authors.affiliation: Department of Pediatrics, University of Parma, Via Gramsci 14, 43100 Parma, Italy. alessandra.vottero@unipr.it
authors.forename: A
authors.initials: A
authors.lastname: Vottero
authors.forename: R
authors.initials: R
authors.lastname: Minari
authors.forename: I
authors.initials: I
authors.lastname: Viani
authors.forename: F
authors.initials: F
authors.lastname: Tassi
authors.forename: F
authors.initials: F
authors.lastname: Bonatti
authors.forename: T M
authors.initials: TM
authors.lastname: Neri
authors.forename: L
authors.initials: L
authors.lastname: Bertolini
authors.forename: S
authors.initials: S
authors.lastname: Bernasconi
authors.forename: L
authors.initials: L
authors.lastname: Ghizzoni
mesh_terms: D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D013196:Dihydrotestosterone / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D052816:Foreskin / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007021:Hypospadias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D008297:Male; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: D011944:Receptors, Androgen; D013196:Dihydrotestosterone