Marfan syndrome, the founding member of connective tissue disorders, is characterized by involvement of three major systems (skeletal, ocular, and cardiovascular) due to alteration in microfibrils. FBN1 at 15q21.1 was found to cause Marfan syndrome in 1991, and in 2004 TGFBR2 at 3p24.1 was newly identified as the Marfan syndrome type II gene. Several studies implied that fibrillin-1 and transforming growth factor-β (TGF-β) signaling are functionally related in extracellular matrix. Identification of TGFBR2 mutations in Marfan syndrome type II provided the direct evidence of the relation in humans.
More than 500 FBN1 mutations have been found in Marfan syndrome, tentative genotype - phenotype correlations have emerged, and mouse models are providing insight into pathogenic mechanisms. TGFBR2 mutations are still limited, however, in 2005 were also reported to cause a new aneurysm syndrome. Functional association between fibrillin-1 and TGF-β signaling in extracellular matrix has been presented.
This review focuses on recent molecular genetics advances in Marfan syndrome and overlapping connective tissue disorders. Mutation spectrum of FBN1 and TGFBR2 in relation to phenotype is presented. Functional relation between fibrillin-1 and TGF-β signaling is discussed. Future prospects in the study of Marfan syndrome are presented.
aINSERM U383, Hôpital Necker-Enfants Malades, Université Paris 5, Paris, France; bLaboratoire de Biochimie, d'Hormonologie et de Génétique Moléculaire, cService de Cardiologie, and dConsultation Multidisciplinaire Marfan, Hôpital Ambroise Paré, AP-HP and UFR, Paris-Ile de France Ouest, Université Versailles-Saint Quentin en Yvelines, Boulogne, France; eDepartment of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; fCREST, Japan Science and Technology Agency, Kawaguchi, Japan; and gDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
This study was supported by grants from INSERM, Université Paris 5, Programme Hospitalier de Recherche Clinique - PHRC AOM 0042, GIS-Maladies Rares (for C B and G J), and from CREST, JST (for T M and N M).
Correspondence to Catherine Boileau, PhD, Laboratoire de Biochimie, d'Hormonologie et de Génétique Moléculaire, Hôpital Ambroise Paré, 9 avenue Charles de Gaulle, 92104 Boulogne cedex, France
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