Genetic Disorders – Development
Kidney International (2004) 66, 10–19; doi:10.1111/j.1523-1755.2004.00703.x
Lack of major involvement of human uroplakin genes in vesicoureteral reflux: Implications for disease heterogeneity
SONGSHAN JIANG, JORDAN GITLIN, FANG-MING DENG, FENG-XIA LIANG, ANDY LEE, ANTHONY ATALA, STUART B BAUER, GARTH D EHRLICH, SALLY A FEATHER, JUDITH D GOLDBERG, JUDITH A GOODSHIP, TIMOTHY H J GOODSHIP, MONIKA HERMANNS, FEN ZE HU, KATRIN E JONES, SUE MALCOLM, CATHY MENDELSOHN, ROBERT A PRESTON, ALAN B RETIK, FRANCIS X SCHNECK, VICTORIA WRIGHT, XIANG Y YE, ADRIAN S WOOLF, XUE-RU WU, HARRY OSTRER, ELLEN SHAPIRO, JUN YU and TUNG-TIEN SUN
Epithelial Biology Unit, Ronald O. Perelman Department of Dermatology, Department of Urology, Department of Pediatrics, Department of Genetics, Department of Pharmacology, and Division of Biostatistics, Kaplan Comprehensive Cancer Center, New York University Medical School, New York, New York; Children's Hospital, Division of Urology/Surgery, Boston, Massachusetts; Alleghey-Singer Research Institute, Center For Genomic Sciences, Pittsburgh, Pennsylvania; Nephro-Urology and Clinical and Molecular Genetics Units, Institute of Child Health, University College London, London, United Kingdom; Institute of Human Genetics, International Centre For Life, Central Parkway, Newcastle-Upon-Tyne, United Kingdom; Department of Urology and Department of Pathology, Columbia University Medical School, New York, New York; and Genome Center and Department of Medicine, University of Washington, Seattle, Washington
Correspondence: Tung-Tien Sun Ph.D, Epithelial Biology Unit, Department of Dermatology, New York University School of Medicine, 550 First Avenue, New York, NY 10016. E-mail: sunt01@med.nyu.edu
Received 22 September 2003; Revised 19 December 2003; Accepted 27 January 2004.
Abstract
Lack of major involvement of human uroplakin genes in vesicoureteral reflux: Implications for disease heterogeneity.
Background
Primary vesicoureteral reflux (VUR) is a hereditary disorder characterized by the retrograde flow of urine into the ureters and kidneys. It affects about 1% of the young children and is thus one of the most common hereditary diseases. Its associated nephropathy is an important cause of end-stage renal failure in children and adults. Recent studies indicate that genetic ablation of mouse uroplakin (UP) III gene, which encodes a 47 kD urothelial-specific integral membrane protein forming urothelial plaques, causes VUR and hydronephrosis.
Methods
To begin to determine whether mutations in UP genes might play a role in human VUR, we genotyped all four UP genes in 76 patients with radiologically proven primary VUR by polymerase chain reaction (PCR) amplification and sequencing of all their exons plus 50 to 150 bp of flanking intronic sequences.
Results
Eighteen single nucleotide polymorphisms (SNPs) were identified, seven of which were missense, with no truncation or frame shift mutations. Since healthy relatives of the VUR probands are not reliable negative controls for VUR, we used a population of 90 race-matched, healthy individuals, unrelated to the VUR patients, as controls to perform an association study. Most of the SNPs were not found to be significantly associated with VUR. However, SNP1 of UP Ia gene affecting a C to T conversion and an Ala7Val change, and SNP7 of UP III affecting a C to G conversion and a Pro154Ala change, were marginally associated with VUR (both P = 0.08). Studies of additional cases yielded a second set of data that, in combination with the first set, confirmed a weak association of UP III SNP7 in VUR (P = 0.036 adjusted for both subsets of cases vs. controls).
Conclusion
Such a weak association and the lack of families with simple dominant Mendelian inheritance suggest that missense changes of uroplakin genes cannot play a dominant role in causing VUR in humans, although they may be weak risk factors contributing to a complex polygenic disease. The fact that no truncation or frame shift mutations have been found in any of the VUR patients, coupled with our recent finding that some breeding pairs of UP III knockout mice yield litters that show not only VUR, but also severe hydronephrosis and neonatal death, raises the possibility that major uroplakin mutations could be embryonically or postnatally lethal in humans.
Keywords:
vesicoureteral reflux (VUR), hydronephrosis, uroplakin, urothelium
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