ABNORMAL FIBRILLIN ASSEMBLY BY DERMAL FIBROBLASTS FROM 2 PATIENTS WITH MARFAN-SYNDROME

The microfibrillar glycoprotein fibrillin is linked to the Marfan synd rome, an autosomal dominant connective tissue disorder. In this study, fibrillin synthesis, deposition and assembly has been investigated in Marfan dermal fibroblast lines from two unrelated patients for whom d istinct mutations in the fibrillin gene FBN1 have been identified. In patient NB, a point mutation has occurred which causes an amino acid s ubstitution and the other patient (GK) has a deletion in one allele. T he two cell lines were broadly comparable with respect to de novo fibr illin synthesis and its distribution between medium and cell layer com partments. Electrophoresis of fibrillin immunoprecipitates confirmed t he presence of fibrillin in medium and cell layers. GK cells secreted an additional higher relative molecular mass fibrillin-immunoreactive component. The timecourse of fibrillin secretion was similar for the t wo lines, but differences in fibrillin aggregation were apparent. Rota ry shadowing electron microscopy of extracted cell layers demonstrated the presence of abundant and extensive microfibrils in NB cell layers . These were abnormal in their gross morphology in comparison to micro fibrils isolated from control cultures. No periodic microfibrillar str uctures were isolated from GK cell layers. These studies underline the need to classify fibrillin defects in terms of biochemical and ultras tructural criteria. Examination of the effects of individual mutations on microfibril organization will be particularly informative in eluci dating the relationship between microfibril dysfunction and the comple x clinical manifestations of Marfan patients.