Abstract
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.
Highlights
To evaluate the participation of the IgE-mast cell axis in CF mouse lethality we bred two different double mutant CF animals, one devoid of mast cells using the C-kitW-sh/W-sh mouse, and a second one using the Stat6−/− animal that is unable to synthetize IgE
Cystic fibrosis phenotype heterogeneity cannot be directly attributed to the type of mutation affecting the gene encoding the CFTR protein
In the case of intestinal obstructions, it has been observed that the recurrence of meconium ileus is higher in affected siblings compared to that in unrelated patients, suggesting that genetic factors influence the manifestation of intestinal disturbances in CF
Summary
To evaluate the participation of the IgE-mast cell axis in CF mouse lethality we bred two different double mutant CF animals, one devoid of mast cells using the C-kitW-sh/W-sh mouse, and a second one using the Stat6−/− animal that is unable to synthetize IgE.
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