Persu Alexandre, Devuyst Olivier, Lannoy Nathalie, Materne Roland, Brosnahan Godela, Gabow Patricia A, Pirson Yves, Verellen-Dumoulin Christine
Division of Nephrology, Université Catholique de Louvain, Medical School, Brussels, Belgium.
Center for Human Genetics and Medical Genetics Unit, Université Catholique de Louvain, Medical School, Brussels, Belgium.
J Am Soc Nephrol. 2000 Dec;11(12):2285-2296. doi: 10.1681/ASN.V11122285.
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.
疾病修饰基因可能参与常染色体显性多囊肾病（ADPKD）中肾脏表型明显的家族内变异性。囊性纤维化（CF）跨膜传导调节因子（CFTR）是一种促进ADPKD中囊内液分泌从而促进囊肿进展的氯离子通道。对编码CFTR的CF基因突变可能与ADPKD中较轻的肾脏表型相关这一假说进行了检验。对117名无亲缘关系的ADPKD先证者和136名未受影响的对照受试者进行了12种最常见突变以及CF基因内含子8多态性TN位点等位基因频率的筛查。ADPKD组（1.7%，n = 2）和对照组（3.7%，n = 5）中CF突变的患病率无显著差异。除一名对照受试者（1717-1G→A）外，所有病例中的CF突变均为ΔF508。ADPKD组和对照组中内含子8的5T、7T和9T等位基因频率也相似。在两名携带CF突变的先证者家族中又检测到两名患有ADPKD和ΔF508突变的患者。这四名患有ADPKD和ΔF508 CFTR（三名杂合子和一名纯合子）的患者以及科罗拉多大学健康科学中心数据库中收集的ADPKD对照患者的肾脏体积和肾功能水平相似。纯合子ΔF508突变缺乏肾脏保护作用可能与CF中缺乏肾脏表型以及ΔF508 CFTR可变的组织特异性表达有关。对一名ADPKD患者的肾脏进行免疫组化分析，该患者为ΔF508纯合子，证实了这一假说，因为在75%的囊肿中检测到CFTR表达（对照ADPKD肾脏中<50%），且至少部分位于囊肿衬里细胞的顶端膜区域。这些数据并不排除某些CFTR突变在ADPKD中具有潜在保护作用，但表明这可能与突变的性质以及突变的CFTR在肾脏中的表达有关。
