THE C1 INHIBITOR GENE AND HEREDITARY ANGIONEUROTIC EDEMA

遗传性血管神经性水肿是一种显性遗传性疾病。 以反复发作的皮肤和粘膜浮肿为特征 膜。累及喉部可能导致死亡，原因是 窒息而死。这种疾病发生在基因杂合的个体中。 调节血浆中蛋白水解酶的抑制物--C1抑制物的缺乏 激活补体和激动素形成系统。缺乏症可能 由于缺乏表达C1抑制物(I型)或由于表达 一种功能失调的突变的C1抑制分子(II型)。总体目标 所提议的项目的目的是定义分子遗传缺陷 导致HANE的C1抑制基因，以描述那些结构 对其功能起重要作用的C1抑制剂的特性，以及 分析C1I抑制基因的转录调控。C1号 两种类型患者的抑制基因(或其相关部分) I型和II型Hane将被克隆和测序。大约15%-20%的I型 由缺失导致的，所有这些似乎都不同于一个 又一个。将对其中的几个进行表征，以定义 它们来自相同或不同的机制。同样，有几个 来自更大的I型患者群体中的个体，没有缺失 将被分析以定义突变类型的分布 产生缺陷。致C1功能障碍的缺陷分析 抑制物(类型II)将集中在那些突变在 活跃的中枢精氨酸。这些功能失调的蛋白质，以及C1INH修饰 在分子中的相同位置进行定点定向突变，将被 体外表达，并对其功能进行分析。其他特定残留物 被认为具有功能重要性的信息将以同样的方式进行分析。 C1I抑制因子在原核系统中的表达及真核表达 C1抑制剂在其氨基末端被截断(它包含大部分 碳水化合物)将用于定义碳水化合物在其 功能。作为功能的另一种探针，以及对C1抑制物的自身抗体 获得性血管性水肿症患者的样本将被用来帮助确定区域 功能所需的分子。氯仿的合成调控 还将检查细胞因子和雄激素抑制物，并将导致 C1INH基因启动子和增强子元件的研究定义 合成调节可能导致其他治疗方法的目标 促进合成，但没有相关的并发症 用目前的治疗方法。

Hereditary angioneurotic edema (HANE) is a dominantly inherited disease characterized by recurrent episodes of edema of the skin and mucous membranes. Involvement of the larynx may result in death due to asphyxiation. The disease occurs in individuals who are heterozygous for deficiency of C1 inhibitor, a plasma protease inhibitor that regulates activation of the complement and kinin-forming systems. Deficiency may result from lack of expression C1 inhibitor (type I) or from expression of a dysfunctional mutant C1 inhibitor molecule (type II). The overall goals of the proposed project are to define the molecular genetic defects in the C1 inhibitor gene that result in HANE, to delineate those structured features of C1 inhibitor that are important for its function, and to analyze the regulation of transcription of the C1 inhibitor gene. The C1 inhibitor gene (or relevant portions thereof) from patients with both type I and type II HANE will be cloned and sequenced. About 15-20% of type I result from deletions, all of which appear to be different from one another. Several of these will be characterized in order to define whether they result from the same or different mechanisms. Similarly, several individuals from the larger group of type I patients without a deletion will be analyzed to define the distribution of the types of mutations that produce deficiency. The analysis of defects resulting in dysfunctional C1 inhibitor (type II) will concentrate on those with mutations outside the active center arginine. These dysfunctional proteins, and C1 INH modified at the same sites in the molecule by site directed mutagenesis, will be expressed in vitro, and their function analyzed. Other specific residues thought to be of functional importance will be analyzed in the same way. C1 inhibitor expressed in a prokaryotic system and eukaryotic expression of C1 inhibitor truncated at its amino terminal end (which contains most of the carbohydrate) will be used to define the role of carbohydrate in its function. As another probe of function, and autoantibody to C1 inhibitor from a patient with acquired angioedema will be used to help define regions of the molecule required for function. The regulation of synthesis of C1 inhibitor by cytokines and androgens also will be examined and will lead to study of promoters and enhancer elements in the C1 INH gene. Definition of synthesis regulation could lead to other therapeutic approaches aimed toward enhancement of synthesis, but without the complications associated with current therapy.