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Project

Unraveling the paradigm of opposing phenotypes due to pathogenic variants in the FBN1 gene.

Marfan syndrome (MFS) and acromelic dysplasias (AD) are caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Remarkably, whereas MFS is characterized by thoracic aortic aneurysms (TAA), tall stature and arachnodactyly, AD patients present with short stature, brachydactyly, and no aortic involvement. Loss of structural integrity of the microfibrils is proposed as the cause of MFS, while altered protein interactions are thought to be at heart of the pathogenesis of AD. However, the alterations in protein interactions identified so far do not seem to fully explain the AD phenotype. Remarkably, increased transforming growth factor beta (TGF-?) signaling has been observed both in human and murine MFS aortic wall tissue and in fibroblasts of AD patients. As such, the exact functional consequences of AD and MFS mutations on cell signaling pathways remain a matter of debate. The main questions therefore remain: (1) which mechanisms explain why TAA is unique to MFS? And (2) why do heterozygous FBN1 mutations, both leading to increased TGF-? signaling, give rise to opposite skeletal phenotypes? In this project, I want to decipher the divergent pathomechanistic processes underlying these contrasting skeletal and aortic phenotypes by applying multi-omics approaches in murine and human (cellular) models of MFS and AD. The expected results may reveal novel therapeutic targets, which is especially important to treat the life-threatening TAA from which MFS patients are suffering.
Date:1 Oct 2021 →  Today
Keywords:ANEURYSMS, SKELETAL GROWTH
Disciplines:Genetics, Cardiac and vascular medicine not elsewhere classified, Musculo-skeletal systems