RESUMO
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.
Assuntos
Síndrome de Marfan/genética , Receptores de Ativinas Tipo I/genética , Dissecção Aórtica/genética , Animais , Aneurisma da Aorta Torácica/genética , Proteínas Contráteis/fisiologia , Bases de Dados Genéticas , Proteínas da Matriz Extracelular/fisiologia , Fibrilina-1 , Fibrilinas , Humanos , Proteínas de Ligação a TGF-beta Latente/genética , Síndrome de Marfan/complicações , Camundongos , Microfibrilas/metabolismo , Proteínas dos Microfilamentos/genética , Modelos Animais , Modelos Biológicos , Desnaturação Proteica/genética , Proteínas Serina-Treonina Quinases , Fatores de Processamento de RNA , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genéticaRESUMO
To elucidate the contribution of the extracellular microfibril-elastic fiber network to vertebrate organogenesis, we generated fibrillin 2 (Fbn2)-null mice by gene targeting and identified a limb-patterning defect in the form of bilateral syndactyly. Digit fusion involves both soft and hard tissues, and is associated with reduced apoptosis at affected sites. Two lines of evidence suggest that syndactily is primarily due to defective mesenchyme differentiation, rather than reduced apoptosis of interdigital tissue. First, fusion occurs before appearance of interdigital cell death; second, interdigital tissues having incomplete separation fail to respond to apoptotic clues from implanted BMP-4 beads. Syndactyly is associated with a disorganized matrix, but with normal BMP gene expression. On the other hand, mice double heterozygous for null Fbn2 and Bmp7 alleles display the combined digit phenotype of both nullizygotes. Together, these results imply functional interaction between Fbn2-rich microfibrils and BMP-7 signaling. As such, they uncover an unexpected relationship between the insoluble matrix and soluble factors during limb patterning. We also demonstrate that the Fbn2- null mutation is allelic to the recessive shaker-with-syndactyly (sy) locus on chromosome 18.
Assuntos
Padronização Corporal/genética , Matriz Extracelular/metabolismo , Deformidades Congênitas dos Membros/genética , Microfibrilas/metabolismo , Proteínas dos Microfilamentos/deficiência , Sindactilia/genética , Fator de Crescimento Transformador beta , Alelos , Animais , Apoptose , Padronização Corporal/efeitos dos fármacos , Proteína Morfogenética Óssea 4 , Proteína Morfogenética Óssea 7 , Proteínas Morfogenéticas Ósseas/deficiência , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Cromossomos/genética , Implantes de Medicamento , Fibrilina-2 , Fibrilinas , Membro Anterior/embriologia , Membro Anterior/patologia , Marcação de Genes , Membro Posterior/embriologia , Membro Posterior/patologia , Deformidades Congênitas dos Membros/patologia , Mesoderma/citologia , Camundongos , Camundongos Knockout , Microfibrilas/patologia , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Transdução de Sinais/genética , Sindactilia/metabolismo , Sindactilia/patologiaRESUMO
Supravalvular aortic stenosis (SVAS), Marfan syndrome (MFS) and Ehlers-Danlos syndrome type IV (EDS IV) are three clinical entities characterized by vascular abnormalities that result from mutations of structural components of the extracellular matrix (ECM). Analyses of naturally occurring human mutations and of artificially generated deficiencies in the mouse have provided insights into the pathogenesis of these heritable disorders of the connective tissue. SVAS is associated with haploinsufficiency of elastin, one of the two major components of the elastic fibers. SVAS is characterized by narrowing of the arterial lumen due to the failure of regulation of cellular proliferation and matrix deposition. Mutations in fibrillin 1 are the cause of dissecting aneurysm leading to rupture of the ascending aorta. Fibrillin-1 is the building block of the microfibrils that span the entire thickness of the aortic wall and are a major component of the elastic fibers that reside in the medial layer. The vascular hallmark of EDS IV is rupture of large vessels. The phenotype is caused by mutations in type III collagen. The mutations ultimately affect the overall architecture of the collagenous network and the biomechanical properties of the adventitial layer of the vessel wall. Altogether, these genotype-phenotype correlations document the diversified contributions of distinct extracellular macroaggregates to the assembly and function of the vascular matrix.