MUTATIONS IN THE CFTR GENE IN PATIENTS WITH CHRONIC SINUSITIS

慢性鼻窦炎是遗传性囊性疾病的显著特征。 纤维化(CF)。纤维素膜跨膜电导功能异常 调控子(CFTR)引起CF，并对该蛋白进行研究 极大地提高了我们对此中的基本缺陷的理解 无序。Cftr起cAMP激活的氯离子通道的作用 调节呼吸系统中另一氯通道的功能 上皮细胞。它在肺的呼吸道中表达，包括 鼻窦衬里的上皮组织。这些观察表明，CFTR 在电解质运动和粘液纤毛运输中起重要作用。 在鼻腔呼吸道上皮中。因此，有可能某些人 CFTR功能的改变可能会改变上皮细胞 易患慢性鼻窦炎的功能。 我们将检验这一假设，即CFTR基因的变异发生在一些 慢性鼻窦炎合并慢性鼻窦炎患者的临床研究 追求以下目标： (1)确定慢性鼻窦炎患者是否有较高的 CF突变的频率高于普通人群。一百 临床中心收集的慢性鼻窦炎患者和任何 有证据表明上皮电解质转运正常的患者 将筛查6个CF常见的突变和10个具有 在患有罕见形式的囊性纤维化的患者中被发现 慢性鼻窦炎的特点。 (2)收集有2名或以上成员患有慢性鼻窦炎的家庭 并确定受影响的个体是否携带相同的CFTR基因 通过使用高度多态的DNA标记与 CFTR基因。 (3)寻找慢性阻塞性肺疾病患者CFTR基因的有害突变 鼻窦炎患者携带一个已知的CF突变(在AIM 1中确定) 以及表现出与CFTR基因连锁的患者(在AIM 2中确认)。 一种称为变性梯度凝胶的突变快速检测方法 将使用电泳法检测每个基因的整个编码区 CFTR基因。 (4)测定CFTR蛋白载体的氯离子转运特性 在慢性鼻窦炎患者中发现突变。突变的cftr基因将 利用Rous肉瘤病毒和An表达呼吸道上皮细胞 腺相关病毒表达系统。CFTR功能将由以下机构评估 氯离子外流和膜片钳研究。

Chronic sinusitis is a prominent feature of the genetic disorder cystic fibrosis (CF). Abnormal function of the CF Transmembrane Conductance Regulator (CFTR) causes CF and investigation of this protein has significantly increased our understanding of the basic defect in this disorder. CFTR functions as a cAMP-activated chloride channel and appears to regulate the function of another chloride channel in respiratory epithelia. It is expressed in the pulmonary airways including the epithelia lining the nasal sinuses. These observations indicate that CFTR plays an important role in electrolyte movement and mucociliary transport in nasal respiratory epithelium. It is therefore plausible that certain alterations of CFTR function may occur that modify epithelial cell function predisposing individuals to the development of chronic sinusitis. We will test the hypothesis that variations in the CFTR gene occur in some patients with chronic sinusitis in the absence of the diagnosis of CF by pursuing the following aims: (1) To determine whether patients with chronic sinusitis have a higher frequency of CF mutations than the general population. One hundred individuals with chronic sinusitis collected by the Clinical Core and any patients who have evidence of a normal epithelial electrolyte transport will be screened for 6 mutations common in CF and 10 mutations that have been found in patients with unusual forms of cystic fibrosis that retain the feature of chronic sinusitis. (2) To collect families in which 2 or more members have chronic sinusitis and determine whether the affected individuals carry the same CFTR genes by performing linkage studies using highly polymorphic DNA markers with the CFTR gene. (3) To search for deleterious mutations in the CFTR genes from chronic sinusitis patients carrying one known CF mutation (identified in Aim 1) and patients demonstrating linkage with CFTR gene (identified in Aim 2). A rapid mutation detection method called denaturing gradient gel electrophoresis will be used to examine the entire coding region of each CFTR gene. (4) To determine the chloride transport properties of CFTR protein bearing mutations found in patients with chronic sinusitis. Mutant CFTR cDNA will be expressed airway epithelial cells using a rous sarcoma virus and an adeno-associated virus expression system. CFTR function will assessed by chloride efflux and patch-clamp studies.