Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse
| Autor: | Amber R. Philp, Francisco V. Sepúlveda, Rodrigo González, L. Pablo Cid, Carlos A. Flores, Texia T. Riquelme, Pamela Millar-Büchner |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cystic Fibrosis lcsh:Medicine Cystic Fibrosis Transmembrane Conductance Regulator Biology Compound heterozygosity Immunoglobulin E Weight Gain Cystic fibrosis Article 03 medical and health sciences KCNN4 medicine Gene silencing Animals Mast Cells Intestinal Mucosa lcsh:Science STAT6 Multidisciplinary Genes Modifier lcsh:R Mast cell medicine.disease Intermediate-Conductance Calcium-Activated Potassium Channels Molecular biology Survival Analysis Mice Inbred C57BL Intestinal Diseases 030104 developmental biology medicine.anatomical_structure Phenotype Mutation biology.protein Cytokines Tumor necrosis factor alpha lcsh:Q Inflammation Mediators STAT6 Transcription Factor Ion Channel Gating |
| Zdroj: | Scientific Reports Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) |
| ISSN: | 2045-2322 |
| Popis: | Nearly 70% of cystic fibrosis (CF) patients bear the phenylalanine-508 deletion but disease severity differs greatly, and is not explained by the existence of different mutations in compound heterozygous. Studies demonstrated that genes other than CFTR relate to intestinal disease in humans and CF-mouse. Kcnn4, the gene encoding the calcium-activated potassium channel KCa3.1, important for intestinal secretion, is present in a locus linked with occurrence of intestinal CF-disease in mice and humans. We reasoned that it might be a CF-modifier gene and bred a CF-mouse with Kcnn4 silencing, finding that lethality was almost abolished. Silencing of Kcnn4 did not improve intestinal secretory functions, but rather corrected increased circulating TNF-α level and reduced intestinal mast cell increase. Given the importance of mast cells in intestinal disease additional double mutant CF-animals were tested, one lacking mast cells (C-kitW-sh/W-sh) and Stat6−/− to block IgE production. While mast cell depletion had no effect, silencing Stat6 significantly reduced lethality. Our results show that Kcnn4 is an intestinal CF modifier gene partially acting through a STAT6-dependent mechanism. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|