FIBRILLIN MUTATIONS IN MARFAN-SYNDROME AND RELATED PHENOTYPES

A casual association has been established between mutations in the fib rillin 1 gene and Marfan syndrome and related phenotypes. Analysis of mutations in these disease types has provided new insights into microf ibril assembly and function. These include evidence for a mutation in a fibrillin 1 domain associated with the severe phenotype; indication of profibrillin processing by a furin-like endoprotease; linkage betwe en extracellular processing and fibrillin 1 polymerization; and involv ement of calcium binding in monomer stabilization and microfibril asse mbly. Identification of intragenic DNA polymorphisms and determination of intron/exon junction sequences have significantly improved our abi lity to diagnose Marfan syndrome and to detect fibrillin 1 mutations. Additional work has provided strong evidence for structural and functi onal heterogeneity of microfibrils. The evidence includes the identifi cation of fibrillin 2, a microfibrillar component structurally related to fibrillin 1;the differential pattern of gene expression of the two fibrillins; and the association of fibrillin 2 mutations with congeni tal contractural arachnodactyly.