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CFTR F508 mutation has minimal effect on the gene expression profile of differentiated human airway epithelia

Departments of ¹Internal Medicine and ²Pediatrics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, ³The University of Iowa Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, Iowa; and ⁴Toronto Lung Transplant Program, University of Toronto, Toronto, Ontario, Canada

Submitted 8 February 2005 ; accepted in final form 2 June 2005

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial chloride channel regulated by phosphorylation. Most of the disease-associated morbidity is the consequence of chronic lung infection with progressive tissue destruction. As an approach to investigate the cellular effects of CFTR mutations, we used large-scale microarray hybridization to contrast the gene expression profiles of well-differentiated primary cultures of human CF and non-CF airway epithelia grown under resting culture conditions. We surveyed the expression profiles for 10 non-CF and 10 F508 homozygote samples. Of the 22,283 genes represented on the Affymetrix U133A GeneChip, we found evidence of significant changes in expression in 24 genes by two-sample t-test (P < 0.00001). A second, three-filter method of comparative analysis found no significant differences between the groups. The levels of CFTR mRNA were comparable in both groups. There were no significant differences in the gene expression patterns between male and female CF specimens. There were 18 genes with significant increases and 6 genes with decreases in CF relative to non-CF samples. Although the function of many of the differentially expressed genes is unknown, one transcript that was elevated in CF, the KCl cotransporter (KCC4), is a candidate for further study. Overall, the results indicate that CFTR dysfunction has little direct impact on airway epithelial gene expression in samples grown under these conditions.

cystic fibrosis transmembrane conductance regulator; airway epithelium

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