A Point Mutation Creating an ExtraN-Glycosylation Site in Fibrillin-1 Results in Neonatal Marfan Syndrome

Fibrillin-1 is a large cysteine-rich glycoprotein of the 10-nm microfibrils in the extracellular matrix. A spectrum of mutations in the fibrillin-1 gene (FBN1) have been identified in patients with Marfan syndrome (MFS), and the majority of mutations resulting in the neonatal and often lethal form of MFS have been identified in the restricted region of exons 24–32 of theFBN1gene. Here we report a novel point mutation in exon 25 of theFBN1gene in a patient with lethal MFS. The mutation resulted in a molecular defect rarely encountered in human diseases, the creation of an extra consensus sequence forN-glycosylation. Metabolic labeling of the patient fibroblast culture andin vitroexpression of the mutagenized cDNA construct suggest that this novelN-glycosylation site is actually utilized. Immunohistochemical and ultrastructural analyses of the fibroblast cultures of the patient show that this excessiveN-glycosylation severely affects microfibril formationin vitro;this finding emphasizes the importance of correct posttranslational modifications of fibrillin molecules for correct aggregation into microfibrillar structures.