FIBRILLIN PATHOLOGY IN THE MARFAN SYNDROMES

马凡氏综合征（MFS），最常见的结缔组织疾病， 其特征是眼部、心血管和骨骼异常。 作为一种常染色体显性遗传性状，它的患病率约为1%。 一万人口。 平均寿命大约是正常人的一半， 主要是心血管并发症。 缺乏临床表型， 目前没有诊断工具来识别受影响的个人。 MFS的临床特征也与其他疾病相同， 不同的组合和不同的程度。 对MFS基因产物的研究已经相对进行了 四十多年来，无数的研究人员一直没有减弱。 我们 免疫组织化学研究表明， 在MFS病因学中的弹性蛋白相关微纤维。 最近，我们 已经证实了这种因果关系，使用分子和遗传 技术. 我们克隆了这个基因，定位在15号染色体上， 首次建立了该基因与MFS之间的直接连锁。 偶然地，我们克隆了另外两个基因，从而证明了 胡萝卜素在分子上是不均匀的。 最重要的是，我们建立了 位于染色体上的一个基因之间的连锁 5，和一个与MFS相关的条件，先天性挛缩性蜘蛛指 （CAA）。 这一原创的、意想不到的发现， 基因和表型相关综合征意味着， 在这些新发现的基质成分中， 结缔组织疾病的常见类型。 我们现在将通过产生以下基因的全长cDNA来扩展这些研究： 5号和15号染色体上的原纤维蛋白，并通过鉴定 选择MFS和CCA患者。 cDNA数据将提供第一个 深入了解这些穷人的结构，关系和演变 以糖蛋白为特征的一组糖蛋白。 基因研究将阐明 这些大分子在结缔组织生理学中的功能。 总之，这些研究将建立一个框架，了解如何 代谢的改变转化为MFS的表型谱 和相关综合征。

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.