PAX2 in human kidney malformations and disease

Harshman, Lyndsay A.; Brophy, Patrick D.

doi:10.1007/s00467-011-2053-0

Cited by 37 publications

(37 citation statements)

References 84 publications

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“…The transcript of most interest from our list was T-UC.300A, which is down-regulated following ATRA treatment (Table 1). This UCR is located within a frequent loss of heterozygosity (LOH) region on chromosome arm 10q, anti-sense to the developmental gene PAX2 , a gene whose under- or over-expression is associated with both pediatric and adult kidney pathology [26]. In addition, T-UC.300A levels were previously shown as up-regulated in colorectal carcinoma tumors [13].…”

Section: Resultsmentioning

confidence: 99%

Expressional alterations in functional ultra-conserved non-coding rnas in response to all-transretinoic acid - induced differentiation in neuroblastoma cells

et al. 2013

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BackgroundUltra-conserved regions (UCRs) are segments of the genome (≥ 200 bp) that exhibit 100% DNA sequence conservation between human, mouse and rat. Transcribed UCRs (T-UCRs) have been shown to be differentially expressed in cancers versus normal tissue, indicating a possible role in carcinogenesis. All-trans-retinoic acid (ATRA) causes some neuroblastoma (NB) cell lines to undergo differentiation and leads to a significant decrease in the oncogenic transcription factor MYCN. Here, we examine the impact of ATRA treatment on T-UCR expression and investigate the biological significance of these changes.MethodsWe designed a custom tiling microarray to profile the expression of 481 T-UCRs in sense and anti-sense orientation (962 potential transcripts) in untreated and ATRA-treated neuroblastoma cell lines (SH-SY5Y, SK-N-BE, LAN-5). Following identification of significantly differentially expressed T-UCRs, we carried out siRNA knockdown and gene expression microarray analysis to investigate putative functional roles for selected T-UCRs.ResultsFollowing ATRA-induced differentiation, 32 T-UCRs were differentially expressed (16 up-regulated, 16 down-regulated) across all three cell lines. Further insight into the possible role of T-UC.300A, an independent transcript whose expression is down-regulated following ATRA was achieved by siRNA knockdown, resulting in the decreased viability and invasiveness of ATRA-responsive cell lines. Gene expression microarray analysis following knockdown of T-UC.300A revealed a number of genes whose expression was altered by changing T-UC.300A levels and that might play a role in the increased proliferation and invasion of NB cells prior to ATRA-treatment.ConclusionsOur results indicate that significant numbers of T-UCRs have altered expression levels in response to ATRA. While the precise roles that T-UCRs might play in cancer or in normal development are largely unknown and an important area for future study, our findings strongly indicate that the function of non-coding RNA T-UC.300A is connected with proliferation, invasion and the inhibition of differentiation of neuroblastoma cell lines prior to ATRA treatment.

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Section: Resultsmentioning

confidence: 99%

Expressional alterations in functional ultra-conserved non-coding rnas in response to all-transretinoic acid - induced differentiation in neuroblastoma cells

et al. 2013

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“…The product of the PAX2 gene, one of the nine members of the family of paired box (PAX) transcription factor genes, plays a critical role in kidney development. [7][8][9] Mutations in this gene have been associated with congenital abnormalities of the kidney and urinary tract (CAKUT) as part of a syndrome known as papillorenal syndrome (PRS) in which ocular manifestations also occur (Mendelian Inheritance in Man, 120330). We report that heterozygous PAX2 mutations account for 4% of adult FSGS and perturb PAX2 function by affecting proper binding to DNA or enhancing its interaction with repressor proteins.…”

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confidence: 99%

Mutations in PAX2 Associate with Adult-Onset FSGS

Barua

Stellacci²,

Stella

et al. 2014

Journal of the American Society of Nephrology

102

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FSGS is characterized by the presence of partial sclerosis of some but not all glomeruli. Studies of familial FSGS have been instrumental in identifying podocytes as critical elements in maintaining glomerular function, but underlying mutations have not been identified for all forms of this genetically heterogeneous condition. Here, exome sequencing in members of an index family with dominant FSGS revealed a nonconservative, disease-segregating variant in the PAX2 transcription factor gene. Sequencing in probands of a familial FSGS cohort revealed seven rare and private heterozygous single nucleotide substitutions (4% of individuals). Further sequencing revealed seven private missense variants (8%) in a cohort of individuals with congenital abnormalities of the kidney and urinary tract. As predicted by in silico structural modeling analyses, in vitro functional studies documented that several of the FSGS-associated PAX2 mutations perturb protein function by affecting proper binding to DNA and transactivation activity or by altering the interaction of PAX2 with repressor proteins, resulting in enhanced repressor activity. Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations. These results expand the phenotypic spectrum associated with PAX2 mutations, which have been shown to lead to congenital abnormalities of the kidney and urinary tract as part of papillorenal syndrome. Moreover, these results indicate PAX2 mutations can cause disease through haploinsufficiency and dominant negative effects, which could have implications for tailoring individualized drug therapy in the future.

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“…Expression patterns of master regulator genes expressed during kidney development were assessed by immunofluorescence and in situ hybridization to identify cells engaged in nephrogenesis. The transcription factor Pax2 is expressed during nephrogenesis and regulates ureteric bud branching and outgrowth (25). The pattern of expression of Pax2 in injured and contralateral control kidneys from P3 to P6 was not affected by cryoinjury.…”

Section: Resultsmentioning

confidence: 99%