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Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B

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Item Type:Article
Title:Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
Creators Name:Becker, T. and Pich, A. and Tamm, S. and Hedtfeld, S. and Ibrahim, M. and Altmüller, J. and Dalibor, N. and Toliat, M.R. and Janciauskiene, S. and Tümmler, B. and Stanke, F.
Abstract:SCNN1B encodes the beta subunit of the epithelial sodium channel ENaC. Previously, we reported an association between SNP markers of SCNN1B gene and disease severity in cystic fibrosis-affected sibling pairs. We hypothesized that factors interacting with the SCNN1B genomic sequence are responsible for intrapair discordance. Concordant and discordant pairs differed at six SCNN1B markers (Praw = 0.0075, Pcorr = 0.0397 corrected for multiple testing). To identify the factors binding to these six SCNN1B SNPs, we performed an electrophoretic mobility shift assay and captured the DNA-protein complexes. Based on protein mass spectrometry data, the epithelial splicing regulatory protein ESRP2 was identified when using SCNN1B-derived probes and the ESRP2-SCNN1B interaction was independently confirmed by coimmunoprecipitation assays. We observed an alternative SCNN1B transcript and demonstrated in 16HBE14o- cells that levels of this transcript are decreased upon ESRP2 silencing by siRNA. Furthermore, we confirmed that mildly and severely affected siblings have different ESPR2 genetic backgrounds and that ESRP2 markers are linked to the response of CF patients' nasal epithelium to amiloride, indicating ENaC involvement (Pbest = 0.0131, Pcorr = 0.068 for multiple testing). Our findings demonstrate that sibling pairs clinically discordant for CF can be used to identify meaningful DNA regulatory elements and interacting factors.
Keywords:Alleles, Alternative Splicing, Binding Sites, Chromosome Mapping, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Susceptibility, DNA Sequence Analysis, Epithelial Cells, Epithelial Sodium Channels, Gene Knockdown Techniques, Genetic Association Studies, Genetic Background, Genotype, Haplotypes, Introns, Modifier Genes, Protein Binding, RNA-Binding Proteins, Siblings, Single Nucleotide Polymorphism
Source:Scientific Reports
Publisher:Nature Publishing Group
Page Range:22447
Date:31 December 2020
Official Publication:https://doi.org/10.1038/s41598-020-79804-y
PubMed:View item in PubMed

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