Role of SLC6A14 as a Modifier of Cystic Fibrosis Phenotype

Cystic Fibrosis (CF) is considered to be a single gene disorder, most commonly the result of a F508del mutation in the CFTR gene. However, patients homozygous for F508del mutation show a considerable variation in disease severity. Consistent with this observation, recent genome wide association studies identified secondary genes that modify disease. A SNP in the putative promoter region of SLC6A14 gene showed the highest significance (p=1.28x10−12). SLC6A14 is a cationic/neutral amino acid transporter, which transports 2Na+, 1 Cl− and a basic/neutral amino-acid into the cell from the apical surface of intestinal/bronchial epithelium. We hypothesize that expression of SLC6A14 is protective against meconium ileus, a CF phenotype detected at birth. To test this hypothesis we over-expressed SLC6A14 in BHK cells stably expressing either WT or F508del-CFTR. We measured CFTR channel activity using the halide sensitive fluorophore, SPQ. We found that CFTR function is enhanced with over-expression of SLC6A14 in cells expressing WT CFTR or F508del CFTR (after rescue of its trafficking defect), (p