Background: Isolated epispadias is the mildest phenotype of the exstrophy-epispadias complex, a urogenital birth defect of variable severity. The androgen receptor antagonist flutamide (FLU) is known to cause malformations in the rat genital and reproductive tract, and single-dose prenatal FLU exposure can induce epispadias in rat offspring. The Cyr61 gene exhibited the highest response to FLU in rat fetal testis, and we suggested it a promising candidate gene for epispadias in humans, because its protein product promotes proliferation, migration, and adhesion of endothelial cells and fibroblasts.
Methods: We used whole mount in situ analysis in mice to investigate ventrocaudal expression of the Cyr61 transcript at gestational days 9.5 to 11.5, which is the equivalent of human gestational weeks 4 to 6 (postulated time of epispadias organogenesis in humans). We also performed mutational analysis of the CYR61 gene in 11 patients with isolated epispadias and in additional eight patients with the related classic bladder exstrophy phenotype.
Results: Expression of Cyr61 was detected in endothelial cells of vessels surrounding the cloaca and the umbilical cord on gestational days 10 and 11.5. The mutation screening, however, revealed no alterations in the coding region of human CYR61.
Conclusions: The spatiotemporal expression pattern observed suggests a role for Cyr61 in the development of the external genitalia. Our mutation screening study, however, could not confirm that mutations affecting the CYR61 gene are a frequent cause of epispadias or classic bladder exstrophy, although rare mutations might be detectable in larger patient samples.
2010 Wiley-Liss, Inc.