Molecular and Cellular Mechanisms of Marfan Syndrome

Dear Colleagues,

Marfan syndrome (MFS) is a rare genetic connective tissue disorder with a prevalence of 1 per 5,000 individuals, and it is caused by variants in the gene encoding for the glycoprotein fibrillin-1 (FBN1). It is inherited in an autosomal dominant manner, but ~25% of the variants are de novo mutations. FBN1 variants induce abnormal or deficient fibrillin-1 fiber formation, affecting the structural integrity of the extracellular matrix (ECM) fibrillary network in a multitude of organs, such as vascular, skeletal, and ocular, hence the occurrence of multisystemic symptoms. Fibrillin-1 has various functions: (1) it forms an independent fibrillary ECM network (microfibrills), (2) it is the core of elastin fibers/lamina, (3) the fibrillin-1 fibers capture a number of multi-signaling growth factors in the ECM, such as the transforming growth factors-beta (TGFβs) and bone morphogenetic proteins (BMPs), and in addition (4) the tail of the premature fibrillin-1 protein that is cleaved off is a peptide hormone called asprosin. This is an adipokine that is mainly released from white adipose tissue during fasting, with glucogenic and orexigenic effects. The effect of an FBN1 variant on this combination of functions likely determines the broad Marfan syndrome phenotype observed in patients. The feared and often lethal complication is aortic dissection and rupture, which mostly occurs after gradual dilatation of the aorta. Aortic dilatation, especially of the aortic root, is present in most MFS patients. In the meantime, the introduction of blood pressure lowering drugs and prophylactic aortic replacement surgery have led to an increase in life expectancy from the age of 40 to 70. However, specific efficient drugs to significantly mitigate or halt aortopathy progression are still lacking, leaving surgical intervention as the current treatment, which is not absent of risks. Since over 3,000 FBN1 variants are described, it is hard to make an individual prognosis of disease onset and development because genotype–phenotype correlations are highly limited. The identification of such relationships can contribute to a more complete understanding of the pathogenesis of aortic disease in Marfan syndrome, improve the risk stratification of patients, and identify new therapeutic targets to recover mechano-sensitive remodeling of the matrix. Hence, more knowledge is essential to understanding the molecular and cellular mechanisms of the different Marfan syndrome symptoms and to improving diagnostic and treatment strategies (pharmacological and gene therapy), which are the topic of this Special Issue on Marfan syndrome.

Dr. Vivian De Waard
Prof. Dr. Gustavo Egea
Dr. María Galán
Guest Editors

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• Marfan syndrome
• aortic aneurysm
• aortic dissection
• TGFβ
• BMP
• matrix metalloproteinase
• NO synthase
• mitochondrial dysfunction
• oxidative stress
• endothelium
• aortic vascular smooth muscle cells
• phenotypic switching
• adventitia
• hemodynamics
• gene therapy
• connective tissue disease