SLC 6 A 14 , an amino acid transporter , modifies the primary 1 CF defect in fluid secretion . 2

The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in 20 the patient population and this variability is partially conferred by the influence of modifier 21 genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid 22 transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current 23 work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice 24 bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the 25 intestinal fluid secretion defect characteristic of these mice. In vitro studies of mouse intestinal 26 organoids revealed that exacerbation of the primary defect was associated with reduced arginine 27 uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP mediated 28 regulation of the major CF-causing mutant protein. Together, these studies highlight the role of 29 this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF 30 mutant and potentially, its promise as a therapeutic target. 31