Recent progress towards a molecular understanding of Marfan syndrome.
Marfan syndrome (MFS) is a systemic disorder of the connective tissue that is inherited as an autosomal dominant trait and which displays variable manifestations in the ocular, skeletal, and cardiovascular systems. These pleiotropic manifestations are accounted for by mutations in fibrillin-1, the building block of extracellular microfibrils. During the past 10 years, we have witnessed significant progress in delineating the pathological events responsible for the manifestations of MFS. Much of this progress has been based on the creation and analysis of fibrillin-1 mutant mouse lines that faithfully recapitulate the spectrum of clinical severity of MFS. These studies have established the critical contribution of fibrillin-1 deficiency to disease progression through altered cell-matrix interactions and dysregulated TGF-beta signaling. As a result, our definition of MFS as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and function of multiple organ systems. Importantly, new biological targets have emerged that may yield exciting new opportunities for the development of productive treatment strategies in MFS.
Dietz
Harry C
HC
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. hdietz@welchlink.welch.jhu.edu
Loeys
Bart
B
Carta
Luca
L
Ramirez
Francesco
F
D000818:Animals; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D020894:Microfibrils / Q000473:pathology*; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D016212:Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse