Molecular genetics of Marfan syndrome.
OBJECTIVE
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-beta (TGF-beta) 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.


RESULTS
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-beta signaling in extracellular matrix has been presented.


CONCLUSIONS
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-beta signaling is discussed. Future prospects in the study of Marfan syndrome are presented.
Boileau
Catherine
C
INSERM U383, Hôpital Necker-Enfants Malades, Université Paris 5, Paris, France. catherine.boileau@apr.aphp.fr
Jondeau
Guillaume
G
Mizuguchi
Takeshi
T
Matsumoto
Naomichi
N
D000818:Animals; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics* / Q000378:metabolism; D020894:Microfibrils / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008967:Molecular Biology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse