title: FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias.
abstract: Hypospadias is a common malformation, which results from failure of urethral tube closure, and whose molecular mechanisms are still largely unknown. The normal genital development is orchestrated by the urethral plate epithelium (UPE), at the genital tubercle (GT), which has polarizing activity, controlling a network of epithelial-mesenchymal interactions, which, when disturbed, may lead to hypospadias. Homeobox proteins (HOXs), fibroblast growth factors (FGFs) and bone morphogenic proteins (BMPs) are essential in this process. Hypospadias in the Hoxa13 -/- mice occurs as a result of the combined loss of Fgf8 and Bmp7 expression in the UPE. In both Fgf10 and Fgfr2 deficient mutant hypospadic male mice, cell proliferation is arrested prematurely and the maturation of the urethral epithelium is disrupted. Fgf8, Fgf10, and their receptor Fgfr2 are downstream targets of androgens (AR) during external genital development, an important fact given the pivotal role of AR in male sex differentiation. Therefore, we examined FGFR2, FGF10, FGF8, and BMP7 as candidate genes for hypospadias. DNA from 60 boys with familial, isolated, hypospadias was screened for mutations in FGFR2, FGF10, FGF8, and BMP7 genes, using DHPLC and DNA sequence analysis. The sequence variations c.590C>G and c.582-62G>A in FGF8, and, c.550+27C>T, c.727+180T>G, c.830T>C (p.Me186Thr), and c.2454C>T in FGFR2 were found uniquely in patients with hypospadias, as compared with 96 controls. No genetic variant in the other genes was detected. These results indicate that mutations are rare in FGF8 and FGFR2 in hypospadias, but gene variants may influence the risk.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. ana.beleza@ki.se
authors.forename: Ana
authors.initials: A
authors.lastname: Beleza-Meireles
authors.forename: Fredrik
authors.initials: F
authors.lastname: Lundberg
authors.forename: Kristina
authors.initials: K
authors.lastname: Lagerstedt
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhou
authors.forename: Davood
authors.initials: D
authors.lastname: Omrani
authors.forename: Louise
authors.initials: L
authors.lastname: Frisén
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002648:Child; D051526:Fibroblast Growth Factor 10 / Q000235:genetics*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007021:Hypospadias / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D014521:Urethra / Q000196:embryology* / Q000503:physiopathology
chemical_list: D019485:Bone Morphogenetic Proteins; C496463:FGF10 protein, human; C496456:FGF8 protein, human; D051526:Fibroblast Growth Factor 10; D051524:Fibroblast Growth Factor 8; D051497:Receptor, Fibroblast Growth Factor, Type 2