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水肿为特征 膜。 喉部受累可能导致死亡， 窒息 该疾病发生在以下个体中： C1抑制剂缺乏，一种调节 激活补体和激肽形成系统。 缺乏可能 由于缺乏表达C1抑制剂（I型）或由于表达 功能障碍的突变型C1抑制剂分子（II型）。 总目标 拟议项目的目的是确定分子遗传缺陷， C1抑制剂基因，导致HANE，以描绘那些结构化的 C1抑制剂的特征对其功能很重要， 分析C1抑制基因的转录调控。 所述C1 来自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。 约15-20%的I型 所有这些似乎都不同于一个 另 其中几个将被描述，以确定是否 它们产生于相同或不同的机制。 同样，几个 没有缺失的I型患者的较大群体中的个体 将进行分析，以确定突变类型的分布， 生产不足。 导致C1功能障碍的缺陷分析 抑制剂（II型）将集中在那些突变以外的 活性中心精氨酸。 这些功能失调的蛋白质和C1 INH修饰的 在分子的相同位点通过定点诱变， 体外表达，并分析其功能。 其他特定残留物 被认为具有功能重要性的将以相同的方式进行分析。 C1抑制剂的原核表达及真核表达 在其氨基末端截短的C1抑制剂（其含有大部分的 碳水化合物）将用于定义碳水化合物在其 功能 作为另一种功能探针，C1抑制剂自身抗体 将使用获得性血管性水肿患者的血液样本来帮助确定 所需的分子结构。 C1合成的调控 也将检查细胞因子和雄激素抑制剂， C1 INH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， 但没有相关的并发症 目前的治疗。

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.