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https://doi.org/10.1371/journal.pone.0056414
Title: | A Remote Cis-Acting Variant at 3q Links Glomerular NCK1 to Diabetic Nephropathy | Authors: | He B. Österholm A.-M. Ojala J.R.M. Andersson A.-C. Tryggvason K. |
Keywords: | luciferase animal cell animal tissue article cell immortalization clinical article controlled study diabetic nephropathy embryo enzyme activity enzyme assay gene gene expression gene expression regulation human human cell immunofluorescence mouse NCK1 gene nonhuman pathogenesis podocyte protein expression reporter gene single nucleotide polymorphism Western blotting zebra fish Adaptor Proteins, Signal Transducing Animals Animals, Genetically Modified Chromosomes, Human, Pair 3 Diabetic Nephropathies Gene Expression Gene Expression Regulation Gene Order Genes, Reporter Genetic Variation Genotype Humans Kidney Glomerulus Mice Oncogene Proteins Polymorphism, Single Nucleotide Regulatory Sequences, Nucleic Acid Zebrafish |
Issue Date: | 2013 | Citation: | He B., Österholm A.-M., Ojala J.R.M., Andersson A.-C., Tryggvason K. (2013). A Remote Cis-Acting Variant at 3q Links Glomerular NCK1 to Diabetic Nephropathy. PLoS ONE 8 (2) : e56414. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0056414 | Rights: | Attribution 4.0 International | Abstract: | We have previously reported genetic association of a single nucleotide polymorphism (SNP), rs1866813, at 3q locus with increased risk of diabetic nephropathy (DN). The SNP is located approximately 70 kb downstream of a cluster of four genes. This raises a question how the remote noncoding polymorphism affects the risk of DN. In this study, we tested a long-range regulatory potential of this variant by a series of experiments. In a luciferase assay, two alleles of the SNP showed differential effects on the luciferase activity in transfected cells in vitro. Using transgenic zebrafish, we further demonstrated in vivo that two alleles of the SNP differentially regulated GFP expression in zebrafish podocytes. Immunofluorescence staining and Western blotting verified that only Nck1 of the four nearby genes was predominantly expressed in mouse glomeruli as well as in podocytes. Furthermore, genotypes of the SNP rs1866813 were correlated with NCK1 expression in immortalized lymphocytes from diabetic patients. The risk allele was associated with increased NCK1 expression compared to the non-risk allele, consistent with the results of the reporter-based studies. Interestingly, differential expression of glomerular Nck1 between mouse strains carrying the nephropathy-prone 129/Sv allele and nephropathy-resistant C57BL/6 allele was also observed. Our results show that the DN-associated SNP rs1866813 is a remote cis-acting variant differentially regulating glomerular NCK1 expression. This finding implicates an important role for glomerular NCK1 in DN pathogenesis under hyperglycemia. © 2013 He et al. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/161342 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0056414 | Rights: | Attribution 4.0 International |
Appears in Collections: | Elements Staff Publications |
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