Abstract

Marfan syndrome (MFS) and other type 1 fibrillinopathies result from mutations in the FBN1 gene, which encodes the connective-tissue microfibrillar protein fibrillin 1. Attempts at correlating genotype with phenotype have suggested considerable heterogeneity. To define the subtype of fibrillinopathy caused by premature termination codon (PTC) mutations, we integrate genotype information and mRNA expression levels with clinical and biochemical phenotypes. By screening the entire FBN1 gene for mutations, we identified 34 probands with PTC mutations. With the exception of two recurrent mutations, these nonsense and frameshift mutations are unique and span the entire FBN1 gene, from IVS2 to IVS63. Allele-specific reverse-transcriptase polymerase chain reaction analyses revealed differential allelic expression in all studied samples, with variable reduction of the mutant transcript. Fibrillin protein synthesis and deposition into the extracellular matrix were studied by pulse-chase analysis of cultured fibroblasts. In the majority of PTC samples, synthesis of normal-sized fibrillin protein was approximately 50% of control levels, but matrix deposition was disproportionately decreased. Probands and mutation-positive relatives were clinically evaluated by means of a standardized protocol. Only 71% (22/31) of probands and 58% (14/24) of the mutation-positive family members met current clinical diagnostic criteria for MFS. When compared with our previously reported study group of 44 individuals with FBN1 cysteine substitutions, the PTC group showed statistically significant differences in the frequency of individual signs, especially in the ocular manifestations. Whereas large-joint hypermobility was more common, lens dislocation and retinal detachment were distinctly less common in the PTC group. We conclude that PTC mutations have a major impact on the pathogenesis of type 1 fibrillinopathies and convey a distinct biochemical, clinical, and prognostic profile.