We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B.
- Authors
Becker, Tim; Pich, Andreas; Tamm, Stephanie; Hedtfeld, Silke; Ibrahim, Mohammed; Altmüller, Janine; Dalibor, Nina; Toliat, Mohammad Reza; Janciauskiene, Sabina; Tümmler, Burkhard; Stanke, Frauke
- 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.
- Subjects
SIBLINGS; SODIUM channels; SINGLE nucleotide polymorphisms; NUCLEOTIDE sequence; IMMUNOPRECIPITATION
- Publication
Scientific Reports, 2020, Vol 10, Issue 1, p1
- ISSN
2045-2322
- Publication type
Article
- DOI
10.1038/s41598-020-79804-y