Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, which affects about 1 in 5,000 individuals, and is caused by mutations in FBN1 gene, which encodes the extracellular matrix protein fibrillin-1. The main clinical manifestations involve the vascular and skeletal systems. Despite complete penetrance, MFS has a great clinical variability, even among individuals from the same family, suggesting the existence of genes modifying the MFS phenotype. In 2016, our group identified loci associated with phenotypic variability in a mouse model for MFS, and we identified the Hspg2 gene as a potential candidate. The Hspg2 gene encodes perlecan protein, a proteoglycan heparan sulfate associated with many vascular and skeletal properties, including the control of the composition of the extracellular matrix, proliferation and differentiation of vascular cells and maintenance of cartilage integrity. Recently, we established a more robust method for phenotyping the MFS mice and defined skeletal and vascular parameters to quantify their phenotypic variability using Principal Component Analysis (PCA). In the preliminary analysis, we suggest that there is a set of skeletal and vascular characteristics that may define the severity of MFS phenotypes, and some of these may be related with perlecan function. Due to the complexity of MFS pathophysiology and the wide functions and interactions mediated by Hspg2 gene, it is difficult to predict the molecular pathways involved in the phenotypic variability. In that way, we aim to generate and analyze RNA sequencing from aorta and spinal column from mildly and severely affected MFS mice in order to detect the differential expressed genes and to dissect their molecular pathways. The identification of genes and pathways involved in the phenotypic variability might not only contribute to the understanding of the molecular pathophysiology but also may contribute to the identification of the relevant physiological events that are associated with mild and severe phenotypes of the disease. (AU)
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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GYURICZA, ISABELA GERDES;
DE SOUZA, RODRIGO BARBOSA;
FARINHA-ARCIERI, LUIS ERNESTO;
FERNANDES, GUSTAVO RIBEIRO;
PEREIRA, LYGIA VEIGA.
Is HSPG2 a modifier gene for Marfan syndrome?.
European Journal of Human Genetics,
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