Evaluation of MRP1-5 gene expression in cystic fibrosis patients homozygous for the delta F508 mutation.
Cystic fibrosis (CF), due to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), exhibits a wide range of disease severity, even among deltaF508 homozygous patients, and the mechanisms of this variability have yet to be elucidated. In view of the close structural homology and possible functional overlap between CFTR and Multidrug Resistance-associated Proteins (MRPs), MRPs were investigated as potentially relevant factors in CF pathophysiology. MRP1-5 gene expression was analyzed in nasal respiratory epithelial cells from deltaF508 homozygous patients (n = 19) and control subjects (n = 20) using semiquantitative RT-PCR. Significantly lower MRP1 and MRP5 transcript levels were found in CF patients than in control subjects. MRP1 and MRP5 transcript levels were strongly correlated (r = 0.71). In CF patients, low MRP1 transcript levels were associated with more severe disease as assessed by the Shwachman score. A relation was also observed between MRP1 levels and presence of a cAMP-independent chloride conductive pathway, as determined by a halide-sensitive fluorescent assay. These results suggest that MRPs, especially MRP1, might play a role in CF phenotype and might therefore constitute a target for a novel pharmacotherapy of CF.
Hurbain
Ilse
I
Service d'Histologie-Biologie Tumorale, UPRES EA3499 Hôpital Tenon, 75020 Paris, France.
Sermet-Gaudelus
Isabelle
I
Vallee
Benoit
B
Feuillet
Marie-Noelle
MN
Lenoir
Gerard
G
Bernaudin
Jean-Francois
JF
Edelman
Aleksander
A
Fajac
Anne
A
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009297:Nasal Mucosa / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation; D013223:Statistics as Topic
D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C505032:CFTR protein, human