FIBRILLIN-1 (FBN1) MUTATIONS IN PATIENTS WITH THORACIC AORTIC-ANEURYSMS

Background Mutations in the FBN1 gene are the cause of the Marfan synd rome, an autosomal dominant disorder with skeletal, ocular, and cardio vascular complications. Aneurysms or dissections of the ascending thor acic aorta are the major cardiovascular complications of the disorder. We rested the hypothesis that FBN1 mutations cause thoracic aortic an eurysms or dissections in patients who do not have the Marfan syndrome . Methods and Results The FBN1 gene was screened for mutations by use of genomic DNA from two patients with thoracic aortic aneurysms who di d not have the Marfan syndrome. Individual FBN1 exons were amplified w ith intron-based exon-specific primers: the DNA fragments were screene d for mutations using single-stranded conformational polymorphism anal ysis, and aberrantly migrating hands were sequenced directly. We ident ified a missense mutation in one patient, D1155N in exon 27. Dermal fi broblasts from the affected individual were used to study the effect o f the missense mutation D1155N on Fibrillin-1 cellular processing. The mutation decreased the amount of fibrillin-1 deposited into the peric ellular matrix. A second putative FBN1 mutation was identified in the second patient, P1837S in exon 44. Although this alteration was not ob served in 234 chromosomes from unrelated individuals, the alteration m ay represent a rare polymorphism. Conclusions Results of these studies support the hypothesis that FBN1 mutations cause thoracic aortic aneu rysms in patients who do not have the Marfan syndrome. This informatio n is important for understanding the pathogenesis of aortic aneurysms and identification of individuals at risk for developing thoracic aort ic aneurysms or dissections.