A miR-1207-5p Binding Site Polymorphism Abolishes Regulation of HBEGF and Is Associated with Disease Severity in CFHR5 Nephropathy

Heparin binding epidermal growth factor (HBEGF) is expressed in podocytes and was shown to play a role in glomerular physiology. MicroRNA binding sites on the 3'UTR of HBEGF were predicted using miRWalk algorithm and followed by DNA sequencing in 103 patients diagnosed with mild or severe glome...

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Vydáno v:	PloS one Ročník 7; číslo 2; s. e31021
Hlavní autoři:	Papagregoriou, Gregory, Erguler, Kamil, Dweep, Harsh, Voskarides, Konstantinos, Koupepidou, Panayiota, Athanasiou, Yiannis, Pierides, Alkis, Gretz, Norbert, Felekkis, Kyriacos N., Deltas, Constantinos
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 02.02.2012 Public Library of Science (PLoS)
Témata:	3' Untranslated regions Algorithms Alleles Anticoagulants Binding Sites Biology Breast cancer Chromosomes Chronic kidney failure Complement System Proteins - genetics Deoxyribonucleic acid Development and progression Diabetes Disease Progression DNA DNA sequencing Epidermal growth factor Gene expression Gene Expression Regulation Gene sequencing Genetic aspects Genetic Therapy Genetics Genomes Glomerulonephritis, Membranous - genetics Glomerulonephritis, Membranous - therapy Health aspects Heparin Heparin-binding EGF-like Growth Factor Heredity Humans Intercellular Signaling Peptides and Proteins - genetics Kidney diseases Kidney Failure, Chronic Laboratories Luciferase Lymphoma Medical research Medicine MicroRNA MicroRNAs MicroRNAs - genetics miRNA Mutation Nephrology Nephropathy Patients Physiological aspects Polymorphism Polymorphism, Genetic Renal failure Ribonucleic acid RNA Rodents Severity of Illness Index Single nucleotide polymorphisms Single-nucleotide polymorphism Target recognition Cyprus
ISSN:	1932-6203, 1932-6203
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Shrnutí:	Heparin binding epidermal growth factor (HBEGF) is expressed in podocytes and was shown to play a role in glomerular physiology. MicroRNA binding sites on the 3'UTR of HBEGF were predicted using miRWalk algorithm and followed by DNA sequencing in 103 patients diagnosed with mild or severe glomerulopathy. A single nucleotide polymorphism, miRSNP C1936T (rs13385), was identified at the 3'UTR of HBEGF that corresponds to the second base of the hsa-miR-1207-5p seed region. When AB8/13 undifferentiated podocytes were transfected with miRNA mimics of hsa-miR-1207-5p, the HBEGF protein levels were reduced by about 50%. A DNA fragment containing the miRSNP allele-1936C was cloned into the pMIR-Report Luciferase vector and co-transfected with miRNA mimics of hsa-miR-1207-5p into AB8/13 podocytes. In agreement with western blot data, this resulted in reduced luciferase expression demonstrating the ability of hsa-miR-1207-5p to directly regulate HBEGF expression. On the contrary, in the presence of the miRSNP 1936T allele, this regulation was abolished. Collectively, these results demonstrate that variant 1936T of this miRSNP prevents hsa-miR-1207-5p from down-regulating HBEGF in podocytes. We hypothesized that this variant has a functional role as a genetic modifier. To this end, we showed that in a cohort of 78 patients diagnosed with CFHR5 nephropathy (also known as C3-glomerulopathy), inheritance of miRSNP 1936T allele was significantly increased in the group demonstrating progression to chronic renal failure on long follow-up. No similar association was detected in a cohort of patients with thin basement membrane nephropathy. This is the first report associating a miRSNP as genetic modifier to a monogenic renal disorder.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: GP KNF CD. Performed the experiments: GP PK KV. Analyzed the data: GP KE HD NG KNF CD. Contributed reagents/materials/analysis tools: NG YA AP. Wrote the paper: KNF CD GP.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0031021