FIBRILLIN PATHOLOGY IN THE MARFAN SYNDROMES

马凡综合征(MFS)是最常见的结缔组织疾病， 以眼部、心血管和骨骼异常为特征。 作为常染色体显性遗传，它的患病率约为1% 一万人口。中位寿命约为正常预期寿命的一半 主要是心血管并发症。缺乏临床表型， 目前还没有诊断工具来识别受影响的个人。 MFS的临床特征也与 不同的组合和不同的程度。 对MFS基因产物的搜索已经相对进行了 四十多年来，无数调查人员有增无减。我们的 免疫组织化学研究表明，纤维蛋白是主要成分 在MFS病因学中，弹性蛋白相关的微纤维。就在最近，我们 已经用分子和基因证实了这种因果关系 技巧。我们克隆了纤维蛋白基因，将其定位在15号染色体上， 首次在该基因与MFS之间建立了直接连锁。 偶然的是，我们克隆了另外两个基因，从而证明了 纤维蛋白在分子上是多相的。最重要的是，我们建立了 位于染色体上的其中一个纤维蛋白基因之间的连锁 5，以及一种与MFS相关的疾病，先天性宫缩性蛛网膜炎 (CAA)。这一原始的和意想不到的发现表明，不同的 纤维蛋白基因和表型相关综合征暗示缺陷 在这些新发现的矩阵中，成分是导致这一点的原因 常见结缔组织病组。 我们现在将通过生成完整大小的cDNA来扩展这些研究 5号和15号染色体上的纤维蛋白，并通过鉴定 选择MFS和CCA患者。Cdna数据将提供第一个 洞察这些劣势的结构、关系和演变 一组特征性的糖蛋白。遗传学研究将阐明 这些大分子在结缔组织生理学中的作用。 总而言之，这些研究将为理解如何 纤维蛋白代谢的改变转化为MFS的表型谱 及相关症状。

The Marfan Syndrome (MFS), the most common disorder of connective tissue, is characterized by ocular, cardiovascular, and skeletal abnormalities. Inherited as an autosomal dominant trait it has a prevalence of about 1 per 10,000 population. Median lifespan is approximately half of normal due primarily to cardiovascular complications. Short of clinical phenotype, there is presently no diagnostic tool to identify affected individuals. The clinical features of MFS are also shared by other conditions in different combinations and at various degrees. The search for the MFS gene product has been carried out relatively unabated, by numerous investigators, for more than forty years. Our immunohistochemical studies have implicated fibrillin, the major component of the elastin-associated microfibrils, in MFS etiology. Very recently, we have confirmed this causal association using molecular and genetic techniques. We cloned the fibrillin gene, mapped it to chromosome 15, and, for the first time, established direct linkage between this gene and MFS. Serendipitously, we cloned two additional genes, thus demonstrating the fibrillin is molecularly heterogeneous. Most significantly, we established linkage between one of these fibrillin genes, which resides on chromosome 5, and an MFS-related condition, congenital contractural arachnodactyly (CAA). This original and unexpected finding of linkage between distinct fibrillin genes and phenotypically related syndromes implies that defects in these newly discovered matrix components are the cause of this rather common group of connective tissue disorders. We will now extend these studies by generating full size cDNAs of fibrillins on both chromosomes 5 and 15, and by identifying mutations in selected MFS and CCA patients. The cDNA data will provide the very first insight into the structure, relationship, and evolution of these poorly characterized group of glycoproteins. the genetic studies will elucidate the function of these macromolecules in connective tissue physiology. Together, these studies will establish the framework for understanding how altered fibrillin metabolism translates into the phenotypic spectrum of MFS and related syndromes.