Background &Aims: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype phenotype stud...Background &Aims: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl-channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. Methods: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)mediated Cl-secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non F508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR mediated Cl-secretion with patients in whom Cl-secretion was absent. Results: Residual anion secretion was detected in 40%of CF patients, and was associated with later disease onset (P <0.0001), higher frequency of PS (P <0.0001), and less severe lung disease (P <0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of 12%-54%of controls. Conclusions: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR mediated Cl-secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.展开更多
文摘Background &Aims: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl-channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. Methods: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)mediated Cl-secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non F508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR mediated Cl-secretion with patients in whom Cl-secretion was absent. Results: Residual anion secretion was detected in 40%of CF patients, and was associated with later disease onset (P <0.0001), higher frequency of PS (P <0.0001), and less severe lung disease (P <0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of 12%-54%of controls. Conclusions: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR mediated Cl-secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.
