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.
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