PHENOTYPE AND GENOTYPE ANALYSIS

囊性纤维化传导调节因子基因的克隆 为阐明囊性癌的基本缺陷提供了一个难得的机会 纤维化(CF)，由此可以设计出合理的治疗方法。表达式 研究表明，cftr是cAMP调节的氯离子通道，并且 主要的CF突变，占突变染色体的70%， 在加工步骤中阻止蛋白质的生物合成。一个世界性的 已经成立了一个联合体，通过以下方式定义所有CFTR突变 对慢性萎缩性胃炎患者的系统分析，到目前为止，确定了400多名 其他不同类型的突变，分布在整个 Cftr基因编码区。虽然这种大量的突变 的结构和功能的丰富信息。 Cftr蛋白，还需要进一步研究来阐明结果。 不同的突变。既往的基因型-表型相关性 申请者进行的研究表明， 胰腺充足的特殊类型的突变，一种轻微的形式 胰腺疾病。这些研究反过来提供了一种功能性的 为进一步进行CFTR的分子表征奠定了基础。这些 调查人员现在提议扩大他们的研究范围，以检查更广泛的 可能有不同类型突变的患者的谱系 CFTR基因。除了非典型的CF患者，他们还将招募 无输精管的不育男性和儿童及幼年男性 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的假设 CFTR基因突变引起的临床症状患者之间的差异 基因突变的部分原因是不同功能类别的CFTR突变； 不同的cftr基因座上的不同的基因类型又会有一个特定的 对受影响阴离子电导缺陷严重程度的影响 上皮性的。本申请的具体目标是：(1)继续 通过在以下人群中鉴定CFTR突变来确定基因类型 有典型临床表现的患者；(2)招募和 描述具有不典型CFs表现的患者组；(3) 确定不同基因型的表型范围和严重程度 类别；以及(4)关联CFTR突变(或突变类别) 具有各种表型。从这些研究中获得的信息 对于理解疾病的可变性是必不可少的 表现形式和开发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.