CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease.
Disease-modifying genes might participate in the significant intrafamilial variability of the renal phenotype in autosomal dominant polycystic kidney disease (ADPKD). Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a chloride channel that promotes intracystic fluid secretion, and thus cyst progression, in ADPKD. The hypothesis that mutations of the CF gene, which encodes CFTR, might be associated with a milder renal phenotype in ADPKD was tested. A series of 117 unrelated ADPKD probands and 136 unaffected control subjects were screened for the 12 most common mutations and the frequency of the alleles of the intron 8 polymorphic TN: locus of CF. The prevalence of CF mutations was not significantly different in the ADPKD (1.7%, n = 2) and control (3.7%, n = 5) groups. The CF mutation was DeltaF508 in all cases, except for one control subject (1717-1G A). The frequencies of the 5T, 7T, and 9T intron 8 alleles were also similar in the ADPKD and control groups. Two additional patients with ADPKD and the DeltaF508 mutation were detected in the families of the two probands with CF mutations. Kidney volumes and renal function levels were similar for these four patients with ADPKD and DeltaF508 CFTR (heterozygous for three and homozygous for one) and for control patients with ADPKD collected in the University of Colorado Health Sciences Center database. The absence of a renal protective effect of the homozygous DeltaF508 mutation might be related to the lack of a renal phenotype in CF and the variable, tissue-specific expression of DeltaF508 CFTR. Immunohistochemical analysis of a kidney from the patient with ADPKD who was homozygous for the DeltaF508 mutation substantiated that hypothesis, because CFTR expression was detected in 75% of cysts (compared with <50% in control ADPKD kidneys) and at least partly in the apical membrane area of cyst-lining cells. These data do not exclude a potential protective role of some CFTR mutations in ADPKD but suggest that it might be related to the nature of the mutation and renal expression of the mutated CFTR.
Persu
Alexandre
A
Division of Nephrology, Université Catholique de Louvain, Medical School, Brussels, Belgium.
Devuyst
Olivier
O
Division of Nephrology, Université Catholique de Louvain, Medical School, Brussels, Belgium.
Lannoy
Nathalie
N
Center for Human Genetics and Medical Genetics Unit, Université Catholique de Louvain, Medical School, Brussels, Belgium.
Materne
Roland
R
Department of Radiology, Université Catholique de Louvain, Medical School, Brussels, Belgium.
Brosnahan
Godela
G
Department of Medicine, Division of Renal Diseases, University of Colorado School of Medicine, Denver, Colorado.
Gabow
Patricia A
PA
Department of Medicine, Division of Renal Diseases, University of Colorado School of Medicine, Denver, Colorado.
Pirson
Yves
Y
Division of Nephrology, Université Catholique de Louvain, Medical School, Brussels, Belgium.
Verellen-Dumoulin
Christine
C
Center for Human Genetics and Medical Genetics Unit, Université Catholique de Louvain, Medical School, Brussels, Belgium.
D000328:Adult; D000368:Aged; D003550:Cystic Fibrosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D050396:TRPP Cation Channels; D014057:Tomography, X-Ray Computed
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D008565:Membrane Proteins; D011506:Proteins; D050396:TRPP Cation Channels; C505032:CFTR protein, human