CF Gene and Cystic Fibrosis Transmembrane Conductance Regulator Expression in Autosomal Dominant Polycystic Kidney Disease ALEXANDRE PERSU,* OLIVIER DEVUYST,* NATHALIE LANNOY, † ROLAND MATERNE, ‡ GODELA BROSNAHAN, § PATRICIA A. GABOW, § YVES PIRSON,* and CHRISTINE VERELLEN-DUMOULIN † *Division of Nephrology, † Center for Human Genetics and Medical Genetics Unit, and ‡ Department of Radiology, Université Catholique de Louvain, Medical School, Brussels, Belgium, and § Department of Medicine, Division of Renal Diseases, University of Colorado School of Medicine, Denver, Colorado. Abstract. Disease-modifying genes might participate in the significant intrafamilial variability of the renal phenotype in autosomal dominant polycystic kidney disease (ADPKD). Cys- tic 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 F508 in all cases, except for one control subject (1717- 1G3 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 F508 mutation were detected in the families of the two probands with CF muta- tions. Kidney volumes and renal function levels were similar for these four patients with ADPKD and F508 CFTR (het- erozygous 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 pro- tective effect of the homozygous F508 mutation might be related to the lack of a renal phenotype in CF and the variable, tissue-specific expression of F508 CFTR. Immunohisto- chemical analysis of a kidney from the patient with ADPKD who was homozygous for the F508 mutation substantiated that hypothesis, because CFTR expression was detected in 75% of cysts (compared with 50% in control ADPKD kid- neys) and at least partly in the apical membrane area of cyst-lining cells. These data do not exclude a potential protec- tive 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. Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited nephropathy, with an estimated prevalence of 1/1000 among Caucasians. The disease is char- acterized by the development of multiple cysts within the kidney, which are inconsistently associated with extrarenal manifestations, including liver and pancreatic cysts and intra- cranial aneurysms. The typical course of ADPKD involves the slow enlargement of renal cysts over decades, leading to end- stage renal disease (ESRD) in the majority of patients (gener- ally near the fifth decade of life) (1). One of the most striking features of ADPKD is substantial interfamilial and intrafamil- ial phenotypic heterogeneity, as evidenced by wide variability in the age at ESRD, ranging from infancy to old age (2,3). Interfamilial phenotypic variability in ADPKD may be ac- counted for by genetic heterogeneity. Mutations in the PKD1 gene (16p13.3) cause the disease in approximately 85% of families (4), and mutations in PKD2 (4q21–23) account for the vast majority of remaining cases (5). Although the phenotypes caused by mutations in PKD1 and PKD2 are very similar, they differ in severity, because ESRD occurs an average of 15 yr earlier in type 1 ADPKD (6). Interfamilial phenotypic variabil- ity in ADPKD could also result from the nature of the mutation itself (7). The severity of renal disease may differ widely among affected members within given families, even between nonidentical twins (8). This could be explained by at least two mechanisms, i.e., a second hit event or modifying genes. Be- cause cyst formation seems to be triggered by a somatic mu- tation in the normal PKD1/PKD2 allele (9,10), the random nature of this phenomenon could provide a valuable explana- tion. However, the existence of modifying loci has been dem- onstrated in animal models of polycystic kidney disease (11,12). These putative modifier genetic backgrounds might affect either cystogenesis itself or clinical conditions (such as hypertension) that are associated with disease progression (13). Received February 23, 2000. Accepted May 2, 2000. Correspondence to Dr. Olivier Devuyst, Division of Nephrology, Université Catholique de Louvain, 10 Avenue Hippocrate, B-1200 Brussels, Belgium. Phone: 32-2-764-18-55; Fax: 32-2-764-28-36; E-mail: devuyst@nefr.ucl.ac.be 1046-6673/1112-2285 Journal of the American Society of Nephrology Copyright © 2000 by the American Society of Nephrology J Am Soc Nephrol 11: 2285–2296, 2000