title: Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans.
abstract: BACKGROUND
  Renal hypodysplasia, characterized by a decrease in nephron number, small overall kidney size, and maldeveloped renal tissue, is a leading cause of chronic renal failure in young children. Familial clustering and renal hypodysplasia phenotypes observed in transgenic animal models suggest a genetic contribution. Uroplakin IIIa (encoded by UPIIIA) is an integral membrane protein present in urothelial plaques, and the murine UPIIIa knockout is associated with urothelial anomalies and vesicoureteral reflux. De novo UPIIIA mutations recently were identified in 4 of 17 patients with severe bilateral renal adysplasia.
  
  
  METHODS
  To evaluate the overall role of UPIIIA in human renal hypodysplasia pathogenesis, we performed UPIIIA mutation analysis in a cohort of 170 pediatric patients affected by severe unilateral or bilateral renal hypodysplasia. Eighty-one patients were affected by bilateral nonobstructive renal hypodysplasia; of these, 61 were without vesicoureteral reflux. Eighty-four patients presented with unilateral nonobstructive renal hypodysplasia, including 24 patients with unilateral multicystic dysplastic kidneys. Family history was positive in 11%.
  
  
  RESULTS
  Mutation analysis showed 2 heterozygous mutations not observed in 200 race-matched control chromosomes. In only 1 family was distribution of the UPIIIA mutation consistent with a disease-causing effect. This de novo missense mutation (Gly202Asp) was identified in a patient with unilateral multicystic dysplastic kidneys. The second (intronically located) mutation appeared unlikely to be disease causing because it did not segregate with an obvious disease phenotype in the affected family.
  
  
  CONCLUSIONS
  Our results indicate that de novo mutations in UPIIIA can be involved in defective early kidney development, but probably constitute only a rare cause of human renal hypodysplasia in a minor subset of individuals.
authors.affiliation: Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schönfelder
authors.forename: Tanja
authors.initials: T
authors.lastname: Knüppel
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.forename: Predrag
authors.initials: P
authors.lastname: Miljkovic
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.forename: Elke
authors.initials: E
authors.lastname: Wühl
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Aysin
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Franz
authors.initials: F
authors.lastname: Schaefer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007668:Kidney / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D021782:Multicystic Dysplastic Kidney / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D014463:Ultrasonography; D014564:Urogenital Abnormalities / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D060171:Uroplakin III
chemical_list: D008562:Membrane Glycoproteins; D060171:Uroplakin III