CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.
OBJECTIVE
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-DeltaF508 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 approximately 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.
Department of Pediatrics and Adolescent Medicine, ALbert Ludwigs University, Freiburg, Germany.
Stephanie
S
Hirtz
Tanja
T
Gonska
Hans H
HH
Seydewitz
Jörg
J
Thomas
Peter
P
Greiner
Joachim
J
Kuehr
Matthias
M
Brandis
Irmgard
I
Eichler
Herculano
H
Rocha
Ana-Isabel
AI
Lopes
Celeste
C
Barreto
Anabela
A
Ramalho
Margarida D
MD
Amaral
Karl
K
Kunzelmann
Marcus
M
Mall
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP