CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis
CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis
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DOI：
10.1053/j.gastro.2004.07.006
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发表时间：
2004-10-01
期刊：
影响因子：
29.4
通讯作者：
Mall, M
中科院分区：
文献类型：
--
作者：
Hirtz, S;Gonska, T;Mall, M
背景与目的：囊性纤维化（CF）是由1000多个囊性纤维化跨膜传导调节基因（CFTR）突变引起的，具有广泛的表型变化。基因型-表型研究发现CFTR突变与胰腺充分性（PS）相关。在异源细胞中发现了残留的Cl通道功能。然而，大多数CFTR突变对天然上皮的功能影响尚不清楚。方法：为了阐明上皮CFTR功能、CFTR基因型和患者表型之间的关系，我们测量了45例CF患者直肠活检标本中环磷酸腺苷（cAMP）介导的Cl-分泌，这些CF患者至少有1个非deltaf508突变，携带广泛的CFTR突变。我们比较了CFTR基因型和CFTR介导的Cl-分泌残留的CF患者与没有Cl-分泌的CF患者的临床表现。结果：40%的CF患者存在阴离子残留分泌，且与发病晚（P < 0.0001）、PS发生率高（P < 0.000:1）、肺部病变轻（P < 0.05）相关。临床结果与剩余CFTR活性的大小相关，其范围与对照组的12%-54%相似。结论：特定的CFTR突变使直肠上皮细胞具有残留的CFTR功能，这与轻度疾病表型密切相关。定量测定直肠CFTR介导的Cl-分泌可能是预测CF疾病预后的一项敏感试验，并可确定CF患者是否受益于增加CFTR残余活性的治疗策略。
Background &Aims: 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 nonDeltaF508 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 < 0.000:1), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of similar to12%-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.