Abstract
The severity of intestinal disease associated with Cystic Fibrosis (CF) is variable in the patient population and this variability is partially conferred by the influence of modifier genes. Genome-wide association studies have identified SLC6A14, an electrogenic amino acid transporter, as a genetic modifier of CF-associated meconium ileus. The purpose of the current work was to determine the biological role of Slc6a14, by disrupting its expression in CF mice bearing the major mutation, F508del. We found that disruption of Slc6a14 worsened the intestinal fluid secretion defect, characteristic of these mice. In vitro studies of mouse intestinal organoids revealed that exacerbation of the primary defect was associated with reduced arginine uptake across the apical membrane, with aberrant nitric oxide and cyclic GMP-mediated regulation of the major CF-causing mutant protein. Together, these studies highlight the role of this apical transporter in modifying cellular nitric oxide levels, residual function of the major CF mutant and potentially, its promise as a therapeutic target.
Highlights
Cystic Fibrosis (CF) is the most common fatal genetic disorder, caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (Kartner et al, 1991; Li et al, 1993; Riordan et al, 1989; Rommens et al, 1989)
We found that the positive effect of arginine on forskolin activated F508del channel function was reduced by pretreatment with the induced NOS (iNOS) inhibitor 1400W in organoids derived from CftrF508del/F508del mice
We found that SLC6A14 is a major arginine transporter on the apical surface of the colonic epithelium and in mice modeling the major CF-causing mutation F508del, and its arginine transport function can ameliorate the basic defect in fluid secretion
Summary
Cystic Fibrosis (CF) is the most common fatal genetic disorder, caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (Kartner et al, 1991; Li et al, 1993; Riordan et al, 1989; Rommens et al, 1989). The CFTR protein is primarily expressed in epithelial cells lining the airways, intestinal tract, and tubular organs, where its anion channel activity on the apical membrane drives fluid transport and modulates the pH of elaborated fluid (Bear et al, 1992; Li et al, 1993; Quinton, 1990; Shah et al, 2016a, 2016b). It is the loss of this channel function, caused by CFTR mutations, that triggers pathogenesis.
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