MUTATIONAL ANALYSIS OF THE CYSTIC FIBROSIS GENE

囊性纤维化（CF）基因编码一种蛋白质， 膜转运分子的超家族，包括多药 抗性基因 肺癌患者CF基因突变分析 研究人员发现，大约70%的CF染色体含有 缺失3个碱基对，导致苯丙氨酸密码子丢失 在氨基酸位置508（deltaF508）处。 通过使用敏感的方法 为了检测突变，我们已经能够识别出一些 基因的改变。 CF患者在以下方面表现出异质性： 胰腺和肺部症状的严重程度。 在某些情况下 可以表明，特定的突变引起轻度胰腺炎， 疾病 该项目的重点是确定的遗传基础， CF患者的异质性，并建立一个动物模型， disorder. 事实上，所有患有CF的男性都因为发育异常而不育 输精管 不育症患者也可见输精管缺如。 没有CF特征症状的男性， 先天性双侧输精管缺如（CBAVD）。 我们有 结果表明，CBAVD的大部分（约一半） 患者是严重CF突变如deltaF508的携带者。 通过 通过对这些个体进行其他突变筛查，我们发现了8种 携带两种CF突变的患者。 因此，CBAVD代表了另一个 由CF基因引起的疾病，或者可以被认为是一种非常温和的形式， 参见 CF肺病的异质性似乎受基因座控制 除了CF。 这一结论是基于以下观察： 具有相同CF基因型的个体在其 肺部疾病的严重程度。 为了测试免疫系统在 对细菌感染的反应，我们已经从HLA基因分型 轻度和重度肺部疾病的CF患者中的位点。 我们找到了一个 DQA基因与肺部疾病严重程度之间存在显著关联， 提示HLA基因座中的一个基因在肺囊性纤维化中起作用， 疾病

The cystic fibrosis (CF) gene codes for a protein that is part of a superfamily of membrane transport molecules that includes the multi-drug resistance genes. Analysis of the mutations in the CF gene in affected individuals has revealed that approximately 70% of CF chromosomes contains a deletion of 3 base pairs, resulting in the loss of a phenylalanine codon at amino acid position 508 (deltaF508). By employing sensitive methods for detecting mutations, we have been able to identify a number of alterations in the gene. CF patients display heterogeneity in the severity of their pancreatic and pulmonary symptoms. In some cases it could be shown that specific mutations give rise to milder pancreatic disease. The focus of this project is to identify the genetic basis of the heterogeneity in CF patients and to develop an animal model for the disorder. Virtually all males with CF are sterile because of an abnormal development of the vas deferens. Absence of the vas deferens is also seen in sterile males who have no symptoms characteristic of CF, a condition known as congenital bilateral absence of vas deferens (CBAVD). We have demonstrated that a large percentage (approximately half) of CBAVD patients are carriers for a severe CF mutation such as deltaF508. By screening these individuals for other mutations, we have identified eight patients that carry two CF mutations. Thus, CBAVD represents another disease caused by the CF gene, or can be thought of as a very mild form of CF. Heterogeneity of CF lung disease appears to be controlled by loci other than CF. This conclusion is based on the observation that individuals with the same CF genotype have great variability in their severity of lung disease. To test for the role of the immune system in the response to bacterial infections, we have typed genes from the HLA locus in CF patients with mild and severe lung disease. We have found a significant association between the DQA gene and severity of lung disease, suggesting that a gene in the HLA locus plays a role in CF pulmonary disease.