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The molecular genetics of Marfan syndrome and related disorders

Abstract

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.

  • BMP, bone morphogenetic protein
  • cbEGF, calcium binding epidermal growth factor
  • CCA, congenital contractural arachnodactyly
  • CMN, cystic medial necrosis
  • CSGE, conformation sensitive gel electrophoresis
  • DHPLC, denaturing high performance liquid chromatography
  • EBP, elastin-binding protein
  • ECM, extracellular matrix
  • HNPCC, hereditary non-polyposis colorectal cancer
  • LAP, latency-associated peptide
  • LDS, Loeys-Dietz aortic aneurysm syndrome
  • LLC, large latent complexes
  • LTBP, latent-TGFβ-binding protein
  • MAGP-1, microfibril-associated glycoprotein-1
  • MFS, Marfan syndrome
  • MFS2, type 2 Marfan syndrome
  • MMP, matrix metalloproteinase
  • MMR, mismatch repair
  • MSI, microsatellite instability
  • NMR, nuclear magnetic resonance
  • PTC, premature termination codon
  • SSCP, single stranded conformation polymorphism
  • TAAD, thoracic ascending aortic aneurysms and dissections
  • TβRII, type II TGFβ receptor
  • TGFβ, transforming growth factor-β
  • UMD, Universal Mutation Database
  • WMS, Weill-Marchesani syndrome
  • fibrillin
  • Marfan syndrome
  • microfibril
  • TGFβ

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Footnotes

  • Published Online First 29 March 2006

  • The authors of this work would like to acknowledge support from Marfan Hilfe (Deutschland) e.V., the Canadian Marfan Association, the National Marfan Foundation (USA), the Deutsche Forschungsgemeinschaft (Grant SFB367-A1), the Canadian Institutes of Health Research (Grant MOP-68836), the Fund for Scientific Research Flanders, the Howard Hughes Medical Institute, National Institutes of Health (AR-41135, AR-049698 and AR-42044), the St Giles Foundation, the James D. Farley Family, the Smilow Center for Marfan Syndrome Research, and the Medical Research Council (G000164)

  • Competing interests: none declared

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