title: Lack of major involvement of human uroplakin genes in vesicoureteral reflux: implications for disease heterogeneity.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Epithelial Biology Unit, Ronald O. Perelman Department of Dermatology, Kaplan Comprehensive Cancer Center, New York University Medical School, New York, New York, USA.
authors.forename: Songshan
authors.initials: S
authors.lastname: Jiang
authors.forename: Jordan
authors.initials: J
authors.lastname: Gitlin
authors.forename: Fang-Ming
authors.initials: FM
authors.lastname: Deng
authors.forename: Feng-Xia
authors.initials: FX
authors.lastname: Liang
authors.forename: Andy
authors.initials: A
authors.lastname: Lee
authors.forename: Anthony
authors.initials: A
authors.lastname: Atala
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Bauer
authors.forename: Garth D
authors.initials: GD
authors.lastname: Ehrlich
authors.forename: Sally A
authors.initials: SA
authors.lastname: Feather
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.forename: Monika
authors.initials: M
authors.lastname: Hermanns
authors.forename: Fen Ze
authors.initials: FZ
authors.lastname: Hu
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Jones
authors.forename: Sue
authors.initials: S
authors.lastname: Malcolm
authors.forename: Cathy
authors.initials: C
authors.lastname: Mendelsohn
authors.forename: Robert A
authors.initials: RA
authors.lastname: Preston
authors.forename: Alan B
authors.initials: AB
authors.lastname: Retik
authors.forename: Francis X
authors.initials: FX
authors.lastname: Schneck
authors.forename: Victoria
authors.initials: V
authors.lastname: Wright
authors.forename: Xiang Y
authors.initials: XY
authors.lastname: Ye
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.forename: Harry
authors.initials: H
authors.lastname: Ostrer
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapiro
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Tung-Tien
authors.initials: TT
authors.lastname: Sun
mesh_terms: D000409:Alanine; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003596:Cytosine; D004622:Embryo, Mammalian / Q000378:metabolism; D005091:Exons; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006147:Guanine; D006801:Humans; D007438:Introns; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011392:Proline; D013941:Thymine; D060170:Uroplakin II; D060171:Uroplakin III; D060167:Uroplakin Ia; D060169:Uroplakin Ib; D019459:Urothelium / Q000196:embryology; D014718:Vesico-Ureteral Reflux / Q000235:genetics*
chemical_list: D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C086451:UPK1A protein, human; C086452:UPK1B protein, human; C554658:UPK2 protein, human; C554659:Upk2 protein, mouse; D060170:Uroplakin II; D060171:Uroplakin III; D060167:Uroplakin Ia; D060169:Uroplakin Ib; D006147:Guanine; D003596:Cytosine; D011392:Proline; D000409:Alanine; D013941:Thymine