PHENOTYPE AND GENOTYPE ANALYSIS

囊性纤维化传导调节因子（CFTR）基因的克隆， 提供了一个独特的机会，以阐明基本缺陷的囊性 纤维化（CF），从而可以设计合理的治疗方法。 表达 研究表明，CFTR作为cAMP调节的氯离子通道发挥作用， 占突变染色体70%的主要CF突变， 在加工步骤中阻断蛋白质的生物合成。 一个世界性 已经建立了一个联盟来定义所有的CFTR突变， 对CF患者进行了系统分析，迄今为止， 不同类型的额外突变，分布在整个 CFTR基因的编码区。 虽然大量的突变 它包含了大量关于结构和功能的信息， CFTR蛋白，需要进一步的研究来阐明结果 不同的突变。 先前基因型-表型相关 申请人进行的研究表明， 特殊类型的突变与胰腺功能不全，一个温和的形式， 胰腺疾病 这些研究反过来提供了一个功能性的 为CFTR的进一步分子表征奠定了基础。 这些 研究人员现在建议扩展他们的研究，以研究更广泛的 可能有不同类型的突变的患者的光谱， CFTR基因 除了非典型CF患者，他们还将招募 输精管缺如的不育男性及儿童和青年 成人急性复发性胰腺炎。 这些研究旨在 检验疾病表现的表型差异 CFTR突变引起的临床疾病患者之间 基因的突变部分是由于CFTR突变的不同功能类别; CFTR基因座上的不同基因型反过来又具有特定的 对受影响的阴离子电导缺陷的严重程度的影响 上皮细胞 本申请的具体目的是（1）继续 通过鉴定CFTR突变来确定基因型， 具有典型CF表现的患者;（2）招募和 表征具有CF非典型表现的患者组;（3） 明确不同基因型表型的范围和严重程度 分类;和（4）关联CFTR突变（或突变的分类） 不同的表型。 从这些研究中获得的信息 对于理解疾病的变异性至关重要 症状和制定适当的疾病治疗方法 诊断、症状前检测、疾病预后和治疗。

The cloning of the cystic fibrosis conductance regulator (CFTR) gene has offered a unique opportunity to elucidate the basic defect of cystic fibrosis (CF) whereby rational therapies can be devised. Expression studies show that CFTR functions as a cAMP-regulated chloride channel and the major CF mutation, which accounts for 70% of mutant chromosomes, blocks the biosynthesis of the protein in a processing step. A worldwide consortium has been established to define all the CFTR mutations by systematic analysis of CF patients and, thus far, identified over 400 additional mutations of different types, distributed over the entire coding region of the CFTR gene. While this large number of mutations holds a wealth of information about the structure and function of the CFTR protein, further studies are required to elucidate the consequence of the different mutations. Previous genotype-phenotype correlation studies performed by the applicants have revealed an association of particular classes of mutations with pancreatic sufficiency, a mild form of pancreatic disease. Those studies have in turn provided a functional basis for further molecular characterization of CFTR. These investigators now propose to extend their study to examine a broader spectrum of patients who may have different kinds of mutations in the CFTR gene. In addition to atypical CF patients, they will recruit infertile males with absence of vas deferens and children and young adults with acute, recurrent pancreatitis. The studies are designed to test the hypothesis that phenotypic differences in disease expression between patients with clinical conditions caused by mutations in the CFTR gene are, in part, due to different functional classes of CFTR mutations; different genotypes at the CFTR locus will, in turn, have a specific effect on the severity of the anionic conductance defect of affected epithelial. The specific aims of this application are (1) to continue to determine the genotypes by identifying CFTR mutations in groups of patients with typical manifestations of CF; (2) to recruit and characterize patient groups with atypical manifestations of CF; (3) to define the range and severity of phenotypes in different genotype classes; and (4) to correlate CFTR mutations (or classes of mutations) with the various phenotypes. The information derived from these studies will be essential for understanding the variability of disease manifestations and for the development of suitable approaches to disease diagnosis, pre-symptomatic testing, disease prognosis and treatment.