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De Novo Uroplakin IIIa Heterozygous Mutations Cause Human Renal Adysplasia Leading to Severe Kidney Failure

Dagan Jenkins^*,, Maria Bitner-Glindzicz, Sue Malcolm, Chih-Chi A. Hu, Jennifer Allison^*, Paul J.D. Winyard^*, Ambrose M. Gullett^*, David F.M. Thomas, Rachel A. Belk, Sally A. Feather, Tung-Tien Sun and Adrian S. Woolf^*

^* Nephro-Urology; Clinical & Molecular Genetics Units, Institute of Child Health, University College London, London, United Kingdom; Ronald O. Perelman Department of Dermatology and Departments of Pharmacology and Urology, New York University School of Medicine, New York, New York; and Departments of Paediatric Urology and Nephrology, St. James’ University Hospital, Leeds, United Kingdom

Address correspondence to: Dagan Jenkins, Nephro-Urology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1E 1EH, UK. Phone: +44-0-20-7905-2663; Fax: +44-0-20-7905-2133; E-mail: d.jenkins{at}ich.ucl.ac.uk

Received for publication September 17, 2004. Accepted for publication March 22, 2005.

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 TG; 1003 TC), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.

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