Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFβ signaling and cell stemness

Abstract

Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients.

Systems pharmacology–based integration of human and mouse data for drug repurposing to treat thoracic aneurysms

“…TAA with ensuing dissection and rupture of the vessel wall is the clinical hallmark of Marfan syndrome (MFS), a relatively common connective tissue disease associated with mutations in the gene that codes for the multifunctional ECM glycoprotein fibrillin-1 (4,5). Fibrillin-1 assemblies (microfibrils and elastic fibers) impart specific physical properties to tissues, distribute mechanical forces within and across them, communicate to multiple types of vessel wall cells through integrin receptors, and modulate local bioavailability of ECM-bound latent TGF-β complexes (5). In spite of significant research effort, the molecular pathogenesis of arterial disease in MFS remains unresolved, therefore hindering advances in drug therapy.…”

Characterization of doxycycline-mediated inhibition of Marfan syndrome-associated aortic dilation by multiphoton microscopy

“…Cardiovascular complications, specifically thoracic aortic aneurysm and dissection, represent the majority of morbidity and mortality factors in MFS 14 . Although the exact molecular pathophysiology of MFS-associated aortic widening is not completely understood, the progressive nature of the disease is generally accredited to the structural abnormality of FBN-1 microfibrils leading to perturbation of the TGF-β signaling cascade and the upregulation of downstream MMPs which contribute to medial degeneration observed in MFS 15 . The vascular abnormalities associated with MFS have been well characterized in both MFS patients and mouse models.…”

Genome Editing for the Understanding and Treatment of Cardiomyopathies

“…Cardiomyopathy is likewise observed in diseases such as Marfan and Barth syndromes. Marfan syndrome is an autosomal dominant disorder with an estimated prevalence of 1:5,000 births [55]. It is caused by mutations in the FBN1 gene that codes for fibrillin-1.…”

“…DCM is typically associated with Marfan syndrome. It is debated whether the dilated phenotype is caused by volume overload related to valvular insufficiency (mitral valve prolapse is commonly seen in patients) or by defects in the cardiac muscle itself [55,57]. On the other hand, Barth syndrome is an X-linked autosomal recessive disorder affecting around 1:300,000-400,000 births, and is caused by mutations in the tafazzin (TAZ) gene [58].…”