Hirtz Stephanie, Gonska Tanja, Seydewitz Hans H, Thomas Jörg, Greiner Peter, Kuehr Joachim, Brandis Matthias, Eichler Irmgard, Rocha Herculano, Lopes Ana-Isabel, Barreto Celeste, Ramalho Anabela, Amaral Margarida D, Kunzelmann Karl, Mall Marcus
Department of Pediatrics and Adolescent Medicine, ALbert Ludwigs University, Freiburg, Germany.
Gastroenterology. 2004 Oct;127(4):1085-95. doi: 10.1053/j.gastro.2004.07.006.
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.
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 non-DeltaF508 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.
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 < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls.
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.
囊性纤维化（CF）由囊性纤维化跨膜传导调节因子（CFTR）基因中的1000多种突变引起，其表型差异很大。基因型-表型研究确定了与胰腺功能正常（PS）相关的CFTR突变。在异源细胞中，已显示某些PS突变具有残余氯离子通道功能。然而，大多数CFTR突变在天然上皮细胞中的功能后果尚未完全明确。
为了阐明上皮细胞CFTR功能、CFTR基因型与患者表型之间的关系，我们检测了45例至少携带1种非ΔF508突变且CFTR突变谱广泛的CF患者直肠活检标本中，环磷酸腺苷（cAMP）介导的氯离子分泌情况。我们比较了有残余CFTR介导的氯离子分泌的CF患者与无氯离子分泌的CF患者的CFTR基因型和临床表现。
40%的CF患者检测到有残余阴离子分泌，这与疾病发病较晚（P<0.0001）、PS发生率较高（P<0.0001）以及肺部疾病较轻（P<0.）相关。临床结果与残余CFTR活性的大小相关，残余CFTR活性约为对照组的12%-54%。
特定的CFTR突变赋予直肠上皮细胞残余CFTR功能，这与较轻的疾病表型密切相关。量化直肠CFTR介导的氯离子分泌可能是预测CF疾病预后以及识别可能从增加残余CFTR活性的治疗策略中获益的CF患者的一项敏感检测方法。
