ALPHA-1-ANTITRYPSIN GENE AND PULMONARY EMPHYSEMA

α-1-抗胰蛋白酶是一种血浆蛋白酶抑制剂， 血液中的总抗蛋白酶活性。 的血清水平降低 这种蛋白质在某些个体中构成一种遗传疾病， α-1-抗胰蛋白酶缺乏症，易使受影响的个体 患上慢性阻塞性肺气肿的风险很高。 的 缺乏症的特征是存在变体α-1-抗胰蛋白酶 Z或S表型而不是正常的M表型，并且 由常染色体隐性遗传性状遗传。 的血清水平 ZZ纯合子和SZ杂合子的α-1-抗胰蛋白酶分别为12%和35% 正常人的不同。 Z和S的频率 在美国，1/3000到1/4000的高加索人是 ZZ表型占100%，SZ表型占1/800。 已经 估计80-90%的ZZ纯合子将发展为肺气肿， 不同的严重程度，并没有治愈这种遗传性疾病， 现在的时间 α-1-抗胰蛋白酶中的细微氨基酸取代 在Z和S缺陷表型与正常M表型之间， 被举报。 由于只有有限的氨基酸序列的正常和 已经确定了变异蛋白，是否有额外的氨基酸 目前还不知道这些蛋白质之间的酸取代 时间 利用重组DNA技术，我们提出了分离和 从正常和缺陷的人α-1-抗胰蛋白酶基因的特征 通过分子克隆。 结构比较 克隆基因之间的组织和核苷酸序列应该揭示 变体蛋白中的任何另外的氨基酸取代， 从而在基因水平上建立了该缺陷的分子基础。 这些信息将允许开发一个简单可靠的 通过基因定位产前诊断遗传病的方法。 早期发现患有遗传性疾病的个体将允许更好地 管理缺陷，这反过来又会降低他们的风险， 在晚年患上肺气肿。 最后，尝试将 为了更好地了解缺陷的原因， 缺陷基因在通过DNA导入后的表达 介导的基因转移到人肝癌细胞系中， 并分泌正常的α-1-抗胰蛋白酶

Alpha-1-antitrypsin is a plasma protease inhibitor that accounts for 90% of the total anti-protease activities in the blood. Reduced serum levels of this protein in certain individuals constitute a genetic disorder known as alpha-1-antitrypsin deficiency, which predisposes affected individuals to high risk of developing chronic obstructive pulmonary emphysema. The deficiency is characterized by the presence of variant alpha-1-antitrypsin of the Z or S phenotypes instead of the normal M phenotype, and is inherited by an autosomal recessive trait. Serum levels of alpha-1-antitrypsin in ZZ homozygotes and SZ heterozygotes are 12 and 35% of the normal individuals, respectively. The frequencies of the Z and S genes are such that 1/3000 to 1/4000 of caucasians in the United States are of the ZZ phenotype and 1/800 are of the SZ phenotype. It has been estimated that 80-90% of ZZ homozygotes will develop pulmonary emphysema of various severity, and there is no cure for this genetic disorder at the present time. Subtle amino acid substitutions in alpha-1-antitrypsin between the Z and S deficient phenotypes and the normal M phenotype have been reported. Since only limited amino acid sequence of the normal and variant proteins have been determined, whether there are additional amino acid substitutions between these proteins are not known at the present time. Using Recombinant DNA Technology, we propose to isolate and characterize the human Alpha-1-antitrypsin gene from normal and deficient individuals by molecular cloning. Comparison of the structural organization and nucleotide sequence between the cloned genes should reveal any additional amino acid substitutions in the variant proteins and would thereby establish the molecular basis of the deficiency at the gene level. This information will then permit the development of a simple and reliable method for prenatal diagnosis of the genetic disorder by gene mapping. Early detection of individuals with the genetic disorder will permit better management of the deficiency, which will in turn reduce the risk of their developing pulmonary emphysema later in life. Finally, attempts will be made to better understand the cause(s) of the deficiency by examining the expression of the deficient genes after their introduction through DNA mediated gene transfer into a human hepatoma cell line which synthesizes and secretes normal Alpha-1-antitrypsin.