e150 fibrillin-1. 6 Fibrillin-1 is a major protein component of extracellular matrix fibrils called microfibrils. Microfibrils are complex structures containing many proteins and are found as isolated aggregates or intimately associated with elastin in elastic fibers. Fibrillin-1 has a complex multidomain structure that includes 47 epidermal growth factor domains, 43 of which have calcium-binding consensus sequences (Figure 1). 7 The protein is encoded by a large gene (230 kb), which is found on chromosome 15 and consists of 65 exons. A second locus for MFS, termed the MFS2 locus, was mapped to 3p24–25, and mutations in the transforming growth factor-receptor type II (TGFBR2) recently have been described in patients with MFS, although the significance of the locus for the phenotype has yet to be determined. 8

More than 100 FBN1 mutations have been described in patients with MFS in the literature, and the UMD-FBN1 mutation database (http://www. umd. be: 2030/) contains 600 FBN1 mutations in individuals with MFS or related conditions (Figure 1). 9 Mutations causing MFS are spread throughout the gene and include missense mutations, nonsense mutations, and exon-splicing errors. Although small genomic deletions involving 2 to 3 exons have been reported, no large deletions have been identified. Only 12% of mutations causing MFS have been observed more than once in unrelated individuals, which complicates molecular diagnoses. At present, neither the location of the mutation nor the type of amino acid altered is sufficient to predict phenotype, with the