Fibrillin mutations in Marfan syndrome and related phenotypes

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Abstract

A casual association has been established between mutations in the fibrillin 1 gene and Marfan syndrome and related phenotypes. Analysis of mutations in these disease types has provided new insights into microfibril 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 between extracellular processing and fibrillin 1 polymerization; and involvement of calcium binding in monomer stabilization and microfibril assembly. Identification of intragenic DNA polymorphisms and determination of intron/exon junction sequences have significantly improved our ability to diagnose Marfan syndrome and to detect fibrillin 1 mutations. Additional work has provided strong evidence for structural and functional heterogeneity of microfibrils. The evidence includes the identification 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 congenital contractural arachnodactyly.

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      One of the first steps in the assembly process of fibrillin-1, a major constituent of microfibrils expressed at the elastic fibers, is its oligomerization into SS bonded multimers, that occurs within a few hours after secretion. This step is followed by the aggregation of fibrillin-1 microfibrils into large microfibrillar bundles (Reinhardt et al., 2000; Ramirez, 1996; Pereira et al., 1997; Pereira et al., 1999; Lin et al., 2002; Charbonneau et al., 2003; Marson et al., 2005). EMILINs are apparently subjected to more complex interactions since after the gC1q-directed homo-trimerization process taking place intracellularly, they form multimers via both non-covalent as well as covalent SS bonds in the extracellular space.

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