Analysis of TSHZ2 and TSHZ3 genes in congenital pelvi-ureteric junction obstruction.
BACKGROUND
Congenital pelvi-ureteric junction obstruction (PUJO) affects 0.3% of human births. It may result from aberrant smooth muscle development in the renal pelvis, resulting in hydronephrosis. Mice that are null mutant for the Teashirt3 (Tshz3) gene exhibit congenital PUJO with defective smooth muscle differentiation and absent peristalsis in the proximal ureter.


METHODS
Given the phenotype of Tshz3 mutant mice, we considered that Teashirt genes, which code for a family of transcription factors, might represent candidate genes for human PUJO. To evaluate this possibility, we used in situ hydridization to analyse the three mammalian Tshz genes in mouse embryonic ureters and determined whether TSHZ3 was expressed in the human embryonic ureter. TSHZ2 and TSHZ3 were sequenced in index cases with non-syndromic PUJO.


RESULTS
Tshz2 and Tshz3 genes were detected in mouse ureters and TSHZ3 was expressed in the human embryonic renal pelvis. Direct sequencing of TSHZ2 and TSHZ3 did not identify any mutations in an initial cohort of 48 PUJO index cases, excluding these genes as a major cause of this condition. A polymorphic missense change (E469G) in TSHZ3 was identified at a residue highly conserved throughout evolution in all Teashirt proteins, although subsequently no significant difference between the E469G allele frequency in Albanian and Macedonian PUJO index cases (3.2%) versus 633 control individuals (1.7%) was found (P = 0.18).


CONCLUSIONS
Mutations in TSHZ2 and TSHZ3 are not a major cause of PUJO, at least in Albanian and Macedonian populations. Expression of these genes in the human fetal ureter emphasizes the importance of analysing these genes in other groups of patients with renal tract malformations.
Jenkins
Dagan
D
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK. dagan.jenkins@imm.ox.ac.uk
Caubit
Xavier
X
Dimovski
Aleksandar
A
Matevska
Nadica
N
Lye
Claire M
CM
Cabuk
Feryal
F
Gucev
Zoran
Z
Tasic
Velibor
V
Fasano
Laurent
L
Woolf
Adrian S
AS
D000415:Albania; D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D018843:Republic of North Macedonia; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014513:Ureter / Q000196:embryology / Q000378:metabolism; D014517:Ureteral Obstruction / Q000151:congenital* / Q000208:ethnology / Q000235:genetics*
D012097:Repressor Proteins; C534111:Teashirt 3 protein, mouse; D014157:Transcription Factors; C489362:Tshz2 protein, mouse