非囊性纤维化支气管扩张症中囊性纤维化跨膜电导调节子通道功能障碍。
Cystic fibrosis transmembrane conductance regulator channel dysfunction in non-cystic fibrosis bronchiectasis.
机构信息
Service d'Explorations Fonctionnelles, Hôpital Cochin, 27 rue du Faubourg St-Jacques, Paris, France.
出版信息
Am J Respir Crit Care Med. 2010 May 15;181(10):1078-84. doi: 10.1164/rccm.200909-1434OC. Epub 2010 Feb 18.
RATIONALE
Although in patients with diffuse bronchiectasis (DB) and a normal sweat test the presence of one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is frequently observed, its pathogenic role in the development of DB remains unclear.
OBJECTIVES
To evaluate the association between CFTR heterozygosity and CFTR protein dysfunction in the airways of patients with DB.
METHODS
Nasal potential difference was measured in 122 patients with DB of unknown origin and with a normal sweat test (Cl(-) < 60 mmol/L). They were classified according to the presence of CFTR mutations: zero (85 patients), one (22 patients), or two mutations (15 patients). Control groups comprised 26 healthy subjects, 38 obligate heterozygotes for CFTR, and 92 patients with classic cystic fibrosis (CF) with an abnormal sweat test (Cl(-) > or = 60 mmol/L). Patients classified as mild-CF were carrying at least one mild mutation and patients classified as severe-CF were homozygous for the F508del mutation.
MEASUREMENTS AND MAIN RESULTS
There was a continuum of airway CFTR dysfunction in the study population as shown by nasal potential difference measurements, ranging from normal values in healthy subjects, to intermediate values in subjects with DB, to highly abnormal values in subjects classified as severe-CF. This continuum of airway CFTR dysfunction was thus strongly associated with defects in the CFTR gene. Moreover, among patients with DB, a similar continuum in intermediate nasal potential difference was identified that was associated with the bearing of zero, one, or two CFTR mutations. These electrophysiological phenotypes and CFTR genotypes were also associated with the clinical phenotype, as shown by the frequency of Staphylococcus aureus and Pseudomonas aeruginosa bronchial colonization.
CONCLUSIONS
Our study supports the hypothesis that a unique CFTR mutation may have pathogenic consequences in patients with DB.
背景
尽管在弥漫性支气管扩张症（DB）患者中，正常汗液检查发现一个囊性纤维化跨膜电导调节因子（CFTR）基因突变较为常见，但该基因突变在 DB 发展中的致病作用仍不清楚。
目的
评估 CFTR 杂合性与 DB 患者气道中 CFTR 蛋白功能障碍之间的关系。
方法
测量了 122 例病因不明且汗液检查正常（Cl(-) < 60mmol/L）的 DB 患者的鼻内电位差。根据 CFTR 基因突变情况进行分类：无突变（85 例）、有一个突变（22 例）或有两个突变（15 例）。对照组包括 26 例健康受试者、38 例 CFTR 强制杂合子和 92 例汗液检查异常（Cl(-) > 60mmol/L）的经典囊性纤维化（CF）患者。轻度 CF 患者至少携带一个轻度突变，重度 CF 患者则为 F508del 突变纯合子。
测量和主要结果
鼻内电位差测量显示，研究人群中存在气道 CFTR 功能障碍的连续谱，从健康受试者的正常值到 DB 患者的中间值，再到被分类为重度 CF 的患者的高度异常值。这种气道 CFTR 功能障碍的连续谱与 CFTR 基因突变缺陷密切相关。此外，在 DB 患者中，也发现了类似的中间鼻内电位差连续谱，与无、有一个或有两个 CFTR 基因突变有关。这些电生理表型和 CFTR 基因型也与临床表型相关，表现为金黄色葡萄球菌和铜绿假单胞菌支气管定植的频率。
结论
我们的研究支持了这样一种假说，即单一 CFTR 突变可能对 DB 患者具有致病作用。
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