Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins, Dagan; Bitner-Glindzicz, Maria; Thomasson, Louise; Malcolm, Sue; Warne, Stephanie A.; Feather, Sally A.; Flanagan, Sarah E.; Ellard, Sian; Bingham, Coralie; Santos, Lane; Henkemeyer, Mark; Zinn, Andrew; Baker, Linda A.; Wilcox, Duncan T.; Woolf, Adrian S.

doi:10.1016/j.jpurol.2006.03.002

« Previous Next »Journal of Pediatric Urology
Volume 3, Issue 1 , Pages 2-9, February 2007

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Dagan Jenkins
- Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN IEH, UK
Maria Bitner-Glindzicz
- Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN IEH, UK
Louise Thomasson
- Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN IEH, UK
Sue Malcolm
- Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN IEH, UK
Stephanie A. Warne
- Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN IEH, UK
Sally A. Feather
- St James' University Hospital, Leeds, UK
Sarah E. Flanagan
- Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
Sian Ellard
- Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
Coralie Bingham
- Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
Lane Santos
- Univesity of Texas Southwestern Medical Center at Dallas, TX, USA
Mark Henkemeyer
- Univesity of Texas Southwestern Medical Center at Dallas, TX, USA
Andrew Zinn
- Univesity of Texas Southwestern Medical Center at Dallas, TX, USA
Linda A. Baker
- Univesity of Texas Southwestern Medical Center at Dallas, TX, USA
Duncan T. Wilcox
- Univesity of Texas Southwestern Medical Center at Dallas, TX, USA
Adrian S. Woolf
- Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN IEH, UK
- Corresponding author. Tel.: +44 20 7905 2615; fax: +44 20 7905 2133.

Received 6 October 2005; accepted 1 March 2006.

Abstract

Objectives

‘Persistent cloaca’ is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice.

Patients and methods

We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association.

Results

Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation.

Conclusion

Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca.

Keywords: Bladder, Gene, Kidney, Mutation, Rectum, Uterus