The autosomal recessive trait cystic fibrosis (CF) is caused by lesions in the CF transmembrane conductance regulator (CFTR) gene. Half of all the CF patients are homozygous for the mutation F508del. F508del CFTR is the most frequent genetic disease causing mutant in Europe. Hence, homozygosity for F508del CFTR provides a unique opportunity to uncover the genetic factors that modulate the course and prognosis in addition to the major underlying genetic lesion. The research project aims to identify the genetic modifiers of residual activity of mutant CFTR and of the expression of the basic defect of impaired epithelial chloride conductance. Wildtype and mutant CFTR of the intestinal human epithelium are characterised at the protein and functional levels. Residual activity of F508del CFTR is recognised by DIDS-insensitive chloride secretory responses in intestinal current measurements. The global expression patterns of intestinal biopsies from F508del homozygous patients with and without residual CFTR activity guide the selection of candidate genes that will be tested in an informative cohort of F508del homozygous patients with extreme phenotypes for association with the electrophysiological phenotype (primary aim) and/or the clinical course and prognosis (secondary aim). Further putative genetic modulators of CF are proteins that regulate the biosynthesis, trafficking, degradation, function or regulation of CFTR: Candidate genes are explored for phenotypically relevant sequence variants by marker geno- and haplotypes. Validated genetic modifiers are characterised in bioassays, particularly in their interaction with members of the CFTR network.