Exp Clin Endocrinol Diabetes 2007; 115 - P02_135
DOI: 10.1055/s-2007-972542

Potential roles of wingless-type-MMTV integration site family, member 2 (WNT2) in human male external genital development

L Franke 1, R Werner 1, A Richter-Unruh 2, KO Schwab 3, O Hiort 1 PM Holterhus 4, BMBF research network on disorders of sex development (DSD)
  • 1University Hospital Schleswig-Holstein, Campus Lübeck, Department of Pediatrics, Lübeck, Germany
  • 2Endokrinologikum, Wattenscheid, Germany
  • 3Freiburg University Hospital, Department of Pediatrics and Adolescence Medicine, Freiburg, Germany
  • 4University Hospital Schleswig-Holstein, Campus Kiel, Department of Pediatrics, Kiel, Germany

In a large part of 46,XY patients with defective external genital differentiation neither alterations of androgen biosynthesis nor of androgen action can be detected. This supports that mechanisms independent from androgen signalling may be involved in male external genital development. Of note, outgrowth of the genital tubercle starts long before the onset of androgen production. HOXA13 mutations in hand-foot-genital syndrome are rare examples of primary defects of genital tubercle development. WNT2 is an intra-cellular signalling molecule that plays roles in sexual differentiation in Drosophila. In a previous microarray-based study, we demonstrated high expression of WNT2 in human foreskin fibroblasts suggesting roles of WNT2 in the human genital tubercle.

Objectives: To screen for mutations in the WNT2 gene in 46,XY patients (pts) with defective external genital differentiation, normal androgen biosynthesis and exclusion of androgen receptor gene defects.

Methods: 35 pts were screened for WNT2 gene alterations. WNT2 gene was divided into 11 fragments and separately amplified by PCR and analysed by single strand conformation polymorphism analysis (SSCP). Pts were compared with 20 normal controls (10 males, 10 females). DNA-fragments with band shifts in SSCP were directly sequenced.

Results: 5 different nucleotide changes of which 3 were known SNPs were detected. 2 novel nucleotide changes were found. 1011 A/G was identified in 10 pts (all heterozygous) but also in 8 of the normal controls (3 homozygous, 5 heterozygous). A heterozygous C/T exchange at base pair 45905 located in the 3'UTR was only detected in one pt with penile hypospadias (heterozygous) but was absent in all other 54 individuals.

Conclusion: Our data do not support a major role of WNT2 in 46,XY pts with defective external genital development. However, since the 3'UTR may influence RNA stability, it cannot be excluded that the unique 45905 C/T nucleotide change might have influenced WNT2 gene dose and therefore contributed to the hypospadias.