REVIEW ARTICLE New insights into the pathogenesis of bladder exstrophyeepispadias complex Istiak Mahfuz a , Tom Darling a , Simon Wilkins a,b , Stefan White a , Wei Cheng a,c,d, * a Monash Institute of Medical Research, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia b Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Australia c Department of Paediatrics, Southern Medical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia d Department of Surgery, Southern Medical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia Received 24 December 2012; accepted 1 May 2013 Available online 3 June 2013 KEYWORDS Bladder exstrophy; P63; PERP; Desmosomes; Development; Gene expression Abstract Bladder exstrophyeepispadias complex (BEEC) is a complex and debilitating congen- ital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothe- lium, and we and others have shown the ShheGlieBmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induc- tion by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) poly- morphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the DNP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the * Corresponding author. Monash Institute of Medical Research, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia. E-mail addresses: wei.cheng3@gmail.com, wei.cheng@monash.edu (W. Cheng). 1477-5131/$36 ª 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpurol.2013.05.001 Journal of Pediatric Urology (2013) 9, 996e1005