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 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 the FBN1 gene. Here we report a novel point mutation in exon 25 of the FBN1 gene 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 for N-glycosylation. Metabolic labeling of the patient fibroblast culture and in vitro expression of the mutagenized cDNA construct suggest that this novel N-glycosylation site is actually utilized. Immunohistochemical and ultrastructural analyses of the fibroblast cultures of the patient show that this excessive N-glycosylation severely affects microfibril formation in vitro; this finding emphasizes the importance of correct posttranslational modifications of fibrillin molecules for correct aggregation into microfibrillar structures.
Lönnqvist
L
L
Department of Human Molecular Genetics, National Public Health Institute, Helsinki, Finland.
Karttunen
L
L
Rantamäki
T
T
Kielty
C
C
Raghunath
M
M
Peltonen
L
L
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D018076:DNA, Complementary; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D006031:Glycosylation; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D054392:Adipokines
D018076:DNA, Complementary; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines