Lack of major involvement of human uroplakin genes in vesicoureteral reflux: Implications for disease heterogeneity

Jiang, Siqi; Gitlin, Jordan; Deng, Fang; Liang, Feng; Lee, Andy; Atala, Anthony; Bauer, Stuart B.; Ehrlich, Garth D.; Feather, Sally; Goldberg, Judith D.; Goodship, Judith A.; Goodship, Timothy H.J.; Hermanns, Monika; Hu, Fang; Jones, Katrin E.; Malcolm, Sue; Mendelsohn, Cathy; Preston, Robert A.; Retik, Alan B.; Schneck, Francis X.; Wright, Victoria; Ye, Xiang Y.; Woolf, Adrian S.; Wu, Xue-Ru; Ostrer, Harry; Shapiro, Ellen; Yu, Jun; Sun, Tung‐Tien

doi:10.1111/j.1523-1755.2004.00703.x

Cited by 50 publications

(45 citation statements)

References 44 publications

(30 reference statements)

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Section: Resultsmentioning

confidence: 99%

“…In particular, the exon 3 variant affecting a C/G conversion and a Pro154Ala change, reported to be associated with primary VUR (30), was found in a heterozygous state in five patients. This is equivalent to an allele frequency of 12.5%, which is slightly lower than the frequency previously reported in controls (16%) and individuals with primary VUR (25%) (30), although no statistical inference can be made from this small, ethnically diverse group. The three previously reported UPIIIA mutations associated with severe bilateral renal adysplasia (20) were not observed in this cohort, and a PCR restriction fragment length polymorphism assay for the 818 C/T mutation showed that while the previously reported Patient 6 (this study) was a heterozygote, all other patients were homozygous for the wild-type allele.…”

Section: Resultsmentioning

confidence: 99%

“…Previously reported UPIIIA coding region single nucleotide polymorphisms (SNPs) (30) were found at nucleotide residues 402 (C/T), 460 (C/G), 549 (A/G), 858 (A/G). In particular, the exon 3 variant affecting a C/G conversion and a Pro154Ala change, reported to be associated with primary VUR (30), was found in a heterozygous state in five patients.…”

Section: Resultsmentioning

confidence: 99%

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Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins

Bitner‐Glindzicz

Thomasson

et al. 2007

Journal of Pediatric Urology

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Objectives-'Persistent cloaca' is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice.Patients and Methods-We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association.Results-Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation.Conclusion-Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins

Bitner‐Glindzicz

Thomasson

et al. 2007

Journal of Pediatric Urology

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“…The candidate gene approach had generally met with limited success in human VUR (e.g., screening of PAX2 or uroplakin genes) (32,33). Lu et al have, however, recently reported disruption of the ROBO2 gene in one patient with a balanced translocation and a phenotype that included VUR; in addition, mutational screening of patients with nonsyndromic VUR revealed two nonconservative amino acid substitutions (19).…”

Section: Discussionmentioning

confidence: 99%

Familial Vesicoureteral Reflux: Testing Replication of Linkage in Seven New Multigenerational Kindreds

Sanna‐Cherchi¹,

Reese²,

Hensle³

et al. 2005

Journal of the American Society of Nephrology

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Vesicoureteral reflux (VUR) (OMIM %193000), a common cause of childhood renal failure, is strongly influenced by hereditary factors. Familial VUR most closely conforms to autosomal-dominant inheritance, but because of variable penetrance and expressivity, large multigenerational pedigrees tractable to linkage analysis have been difficult to ascertain. A single genome-wide study of familial VUR has demonstrated linkage to chromosome 1p13, with 78% locus heterogeneity. Previous studies in humans have also suggested loci on chromosomes 6p21, 10q26, and 19q13, whereas mutations in ROBO2 were recently reported in some patients with VUR. Replication of these studies was attempted in seven previously undescribed families from Italy and the United States. Simulation studies, assuming 50% locus heterogeneity, showed that these kindreds had 85% power to replicate linkage and 53% power to achieve genome-wide significance at candidate intervals. Thirty-five markers on chromosomes 1p13, 3p12, 6p21, 10q26, and 19q13 were genotyped and analysis of linkage under a variety of models was performed. Parametric analysis excluded linkage to all candidate loci under genetic homogeneity; moreover, the data did not support statistically significant linkage under models of locus heterogeneity. Similarly, nonparametric, allele-sharing analysis did not reveal any evidence of linkage at any of the loci tested. Thus, despite sufficient power, linkage of familial VUR to previously reported candidate intervals could not be replicated. These data demonstrate substantial genetic heterogeneity of VUR and suggest that mapping strategies relying on a large number of kindreds or single "loaded" pedigrees will be most effective to achieve replication or detection of linkage.

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“…Mutations in UPK3A have recently been found in some patients with renal aplasia, hypoplasia and dysplasia, including some who had vur. 121,122 By contrast, other investigators found no evidence for major involvement of UPK3A in vur, [123][124][125][126] but concede that their results do not rule out mutations in regulatory elements affecting gene expression or function. 123,126 The X chromosome some strong candidate genes on the X chromosome (KAL1 and AGT2R) as well as reports of X-linked transmission and evidence suggesting linkage of primary vur to the pseudoautosomal region 22 led Kelly et al 125 to investigate the possibility of linkage in these areas in a study in 2009.…”

Section: N a T U R E R E V I E W S U N C O R R E C T E D P R O O Fmentioning

confidence: 89%

Genetics of vesicoureteral reflux

et al. 2011

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| Primary vesicoureteral reflux (VUR) is the most common urological anomaly in children, affecting 1-2% of the pediatric population and 30-40% of children presenting with urinary tract infections (UTIs). Refluxassociated nephropathy is a major cause of childhood hypertension and chronic renal failure. The hereditary and familial nature of VUR is well recognized and several studies have reported that siblings of children with VUR have a higher incidence of reflux than the general pediatric population. Familial clustering of VUR implies that genetic factors have an important role in its pathogenesis, but no single major locus or gene for VUR has yet been identified and most researchers now acknowledge that VUR is genetically heterogeneous. Improvements in genome-scan techniques and continuously increasing knowledge of the genetic basis of VUR should help us to further understand its pathogenesis.

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Lack of major involvement of human uroplakin genes in vesicoureteral reflux: Implications for disease heterogeneity

Cited by 50 publications

References 44 publications

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Familial Vesicoureteral Reflux: Testing Replication of Linkage in Seven New Multigenerational Kindreds

Genetics of vesicoureteral reflux

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