A POINT MUTATION CREATING AN EXTRA N-GLYCOSYLATION SITE IN FIBRILLIN-1 RESULTS IN NEONATAL MARFAN-SYNDROME

Fibrillin-1 is a large cysteine-rich glycoprotein of the 10-nm microfi brils in the extracellular matrix. A spectrum of mutations in the fibr illin-1 gene (FBN1) have been identified in patients with Marfan syndr ome (MFS), and the majority of mutations resulting in the neonatal and often lethal form of MFS have been identified in the restricted regio n of exons 24-32 of the FBN1 gene. Here we report a novel point mutati on in exon 25 of the FBN1 gene in a patient with lethal MFS. The mutat ion resulted in a molecular defect rarely encountered in human disease s, the creation of an extra consensus sequence for N-glycosylation. Me tabolic labeling of the patient fibroblast culture and in vitro expres sion of the mutagenized cDNA construct suggest that this novel N-glyco sylation site is actually utilized. Immunohistochemical and ultrastruc tural analyses of the fibroblast cultures of the patient show that thi s excessive N-glycosylation severely affects microfibril formation in vitro; this finding emphasizes the importance of correct posttranslati onal modifications of fibrillin molecules for correct aggregation into microfibrillar structures. (C) 1996 Academic Press, Inc.