MUTATIONAL ANALYSIS OF THE CYSTIC FIBROSIS GENE

囊性纤维化(CF)是由囊性纤维化突变引起的 跨膜电导调节因子(CFTR)基因。CFTR编码一种蛋白质 这是膜运输分子超家族的一部分，而CF 患者表现出许多分泌器官的异常，特别是 肺和胰腺。已发现250多种不同的突变 该基因最常见的是3个碱基对的缺失，导致 氨基酸508位的苯丙氨酸密码子丢失(DeltaF508)。 CF患者的症状严重程度具有高度的异质性。虽然 一些突变只出现在轻度胰腺疾病的患者中， 肺部症状的严重程度与 患者的基因分型。这个项目的重点是识别基因 慢性萎缩性胃炎患者的异质性基础及其他特征 可能由CFTR引起的遗传性疾病。除 CF患者的肺和胰腺缺陷，几乎所有的CF男性都是 不孕不育。我们之前已经证明，患有不孕症的男性 先天性双侧输精管缺如(CBAVD) Cf基因突变。换句话说，CBAVD可能代表着一种较温和的 CF的格式。通过收集更大的CBAVD患者样本，我们已经 能够扩展和确认这一发现。另一个症状是 与CF相关的是胰腺炎，这是一种与胰腺相关的疾病 有严重的腹痛，血清酶水平异常，以及胰腺 纤维化症。虽然导致胰腺炎的原因很多，但至少有一个原因 形式是遗传的。遗传性胰腺炎是一种常染色体显性遗传病 儿童时期起病的精神障碍。为了调查 HP可能是由CF基因的改变引起的，我们有 分析了一个惠普家族的CFTR基因突变。该基因的一个突变 在这个家庭中被确认，这两个受影响的母亲都存在 还有她的儿子。这种突变发生在蛋白质的残留物中，这表明 许多物种的CFTR基因之间的保守性，表明它是 对基因的功能很重要。

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR encodes a protein that is part of a superfamily of membrane transport molecules, and CF patients display abnormalities in many secretory organs, particularly the lungs and pancreas. Over 250 different mutations have been identified in the gene, the most common being a deletion of 3 base pairs, resulting in the loss of a phenylalanine codon at amino acid position 508 (deltaF508). The severity of symptoms in CF patients is highly heterogeneous. Although some mutations appear only in patients with mild pancreatic disease, the severity of pulmonary symptoms does not show a correlation with the patients genotype. The focus of this project is to identify the genetic basis of the heterogeneity in CF patients and to characterize other genetic disorders that may be caused by CFTR. In addition to the pulmonary and pancreatic defects in CF patients, nearly all CF males are infertile. We have previously shown that sterile males with a condition known as congenital bilateral absence of vas deferens (CBAVD) have mutations in the CF gene. In other words, CBAVD may represent a milder form of CF. By collecting a larger sample of CBAVD patients we have been able to extend and confirm this finding. Another symptom that is associated with CF is pancreatitis, a disorder of the pancreas associated with severe abdominal pain, abnormal serum enzyme levels, and pancreatic fibrosis. Although there are many causes of pancreatitis, at least one form is hereditary. Hereditary pancreatitis (HP) is an autosomal dominant disorder with onset of the disease in childhood. To investigate the possibility that HP could be caused by alterations in the CF gene, we have analyzed an HP family for CFTR gene alterations. A mutation in the gene was identified in this family that was present in both the affected mother and her son. This mutation occurs in a residue of the protein which shows conservation between the CFTR genes of many species, suggesting that it is important for the function of the gene.