ELASTIN GENE DEFECTS IN PSEUDOXANTHOMA ELASTICUM

该提案的目的是确定弹性蛋白基因的突变 导致遗传性疾病的发病机制 皮肤、眼和血管组织，弹性假黄瘤（PXE）。 PXE是一种遗传性疾病， 几种弹性组织中的钙化弹性纤维，包括皮肤， 动脉和视网膜的弹性布鲁赫膜。 畸变弹性 这些组织中的纤维沉积是导致 PXE的临床症状特征。 这些症状包括视网膜 出血和相关的失明、丘疹、无弹性皮肤病变， 心血管异常，包括高血压和间歇性 跛行。 过去几年的一些调查人员认为 弹性纤维蛋白缺陷在发育中的功能作用 的PXE。 然而，迄今为止没有直接证据表明， 任何基因突变的存在负责这种遗传弹性 纤维缺陷 弹性蛋白是弹性纤维的主要蛋白质成分。 这种不溶性 并且广泛交联的蛋白质由可溶性前体组装， 在本申请中，我们提供了第一个直接的弹性蛋白原。 证据表明原弹性蛋白基因存在突变 这是一个占主导地位的，表型严重形式的PXE负责。 我们 现在希望在几个PXE中描述原弹性蛋白基因的突变 患者以确定该基因的突变是否是导致 这种弹性组织疾病的特殊表型特征。 PXE是一种典型的弹性纤维疾病;表型类似于许多 更复杂的弹性组织疾病的特征。 一 详细了解弹性蛋白原与 基因突变和PXE表型将为 了解弹性纤维结构缺陷在疾病中的作用 从衰老到高血压和主动脉瘤

The aim of this proposal is to identify the mutations in the elastin gene that are responsible for the pathogenesis of a heritable disorder of cutaneous, ocular and vascular tissue, pseudoxanthoma elasticum (PXE). PXE is a genetic disease characterized by the accumulation of abnormal, calcified elastic fibers in several elastic tissues, including skin, arteries and the elastic Bruch's membrane of the retina. Aberrant elastic fiber deposition in these tissues is responsible for the development of the clinical symptoms characteristic of PXE. These symptoms include retinal hemorrhage and associated blindness, papula, inelastic skin lesions and cardiovascular abnormalities that include hypertension and intermittent claudication. Several investigators over the last few years have suggested a functional role for defects in elastic fiber proteins int he development of PXE. However, there has been no direct evidence to date suggesting the presence of any gene mutation(s) responsible for this heritable elastic fiber defect. Elastin is the major protein component of elastic fibers. This insoluble and extensively cross-linked protein is assembled from a soluble precursor, tropoelastin, In this application, we have provided the first direct evidence demonstrating the presence of a mutation in the tropoelastin gene that is responsible for a dominant, phenotypically severe form of PXE. We now hope to characterize mutations in the tropoelastin gene in several PXE patients to determine whether mutations in this gene are responsible for particular phenotypic characteristics of this elastic tissue disorder. PXE is a prototypic elastic fiber disease; the phenotype resembles many of the characteristics of more complex disorders of elastic tissue. A detailed understanding of the functional relationship between tropoelastin gene mutations and the PXE phenotype will provide an important basis for understanding the role of structural defects in elastic fibers in disorders ranging from aging to hypertension and aortic aneurysms.