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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 K Ca 3.1, 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-kit  W-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.

Kcnn4 is a modifier gene of intestinal cystic fibrosis preventing lethality in the Cftr-F508del mouse