Mutation analyses of Uroplakin II in children with renal tract malformations.
BACKGROUND
Uroplakin (UP) proteins cover urothelial apical surfaces. Mice lacking UPIIIa have elevated urothelial permeability and congenital renal tract anomalies, and UPIIIa mutations have been reported in children with kidney and ureter malformations. Mice with null mutation of another UP family member, UPII, are often born with congenital hydronephrosis. We hypothesized that UPII mutations may be present in humans with renal tract malformations.


METHODS
Mutations were sought, using direct sequencing of the five UPII exons, in 42 children with diverse renal tract anomalies.


RESULTS
No UPII abnormalities were detected in 41 patients, whereas one index case had a heterozygous frameshift change which, if expressed, would generate a truncated protein. This Caucasian child presented with vesicoureteric reflux (VUR), bilateral nephropathy and renal failure. The genetic change was also found in the index case's mother who had normal renal ultrasonography, but it was absent in 150 healthy Caucasian control individuals (96 assessed by direct sequencing and another 54 assessed by restriction digests). UPII was immunolocalized in urothelium of the normal human embryonic renal pelvis in a pattern similar to UPIIIa.


CONCLUSIONS
This study offers no definitive support for UPII mutations causing human renal tract malformations. In rare patients, UPII variants might be implicated in pathogenesis when acting in conjunction with other yet-to-be-defined, genetic or environmental modifying factors.
Jenkins
Dagan
D
Nephro-Urology Unit, UCL Institute of Child Health, London, WCIN IEH, UK. dagan.jenkins@imm.ox.ac.uk
Bitner-Glindzicz
Maria
M
Malcolm
Sue
S
Allison
Jennifer
J
de Bruyn
Rose
R
Flanagan
Sarah
S
Thomas
David F M
DF
Belk
Rachel A
RA
Feather
Sally A
SA
Bingham
Coralie
C
Southgate
Jennifer
J
Woolf
Adrian S
AS
D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007668:Kidney / Q000002:abnormalities*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D051437:Renal Insufficiency / Q000235:genetics; D060170:Uroplakin II
D008565:Membrane Proteins; C554658:UPK2 protein, human; C554659:Upk2 protein, mouse; D060170:Uroplakin II