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The molecular genetics of Marfan syndrome and related disorders

¹ Institute of Medical Genetics, Charité University Hospital, Humboldt University, Berlin, Germany
² Department of Pediatrics, Mount Sinai School of Medicine-New York University, One Gustave L. Levy Place, New York, NY 10029, USA
³ Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK
⁴ Laboratoire de Génétique Moléculaire, Institut Universitaire de Recherche Clinique, Montpellier, France
⁵ Institute of Integrative and Comparative Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
⁶ Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium
⁷ Departments of Pediatrics, Medicine and Molecular Biology and Genetics, and Howard Hughes Medical Institute, John Hopkins University School of Medicine, Baltimore, MD, USA
⁸ Division of Molecular and Cellular Biochemistry, Department of Biochemistry, University of Oxford, Oxford, UK
⁹ Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
¹⁰ Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA
¹¹ Laboratory of Genetics and Organogenesis, Research Division of the Hospital for Special Surgery and Department of Physiology and Biophysics at the Weill Medical College of Cornell University, New York, NY, USA
¹² McGill University, Department of Anatomy and Cell Biology and Faculty of Dentistry, Montreal, Canada
¹³ Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, NE, USA

Correspondence to:
Dr Peter N Robinson
Institute of Medical Genetics, Charité University Hospital, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany; peter.robinson{at}charite.de] 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.

Abbreviations: 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-TGFß-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; TßRII, type II TGFß receptor; TGFß, transforming growth factor-ß; UMD, Universal Mutation Database; WMS, Weill-Marchesani syndrome

Keywords: fibrillin; Marfan syndrome; microfibril; TGFß

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