Analysis of the role of Hspg2 gene in the variability of skeletal and vascular phenotypes in Martan Syndrome

Author(s)

Isabela Gerdes Gyuricza

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2019-10-02

Examining board members

Lygia da Veiga Pereira Carramaschi; Francisco Rafael Martins Laurindo; Ana Beatriz Alvarez Perez; Carla Rosenberg

• Advisor: Lygia da Veiga Pereira Carramaschi

Abstract

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 include aneurysms and aortic rupture and skeletal phenotypes, such as excessive growth of bones and scoliosis. Despite complete penetrance, MFS has a large clinical variability, even between individuals with the same mutation, indicating the existence of modifier genes. Recently, our group has identified loci associated with skeletal and vascular variability in a murine model of the syndrome. Among the genes within one of the loci associated with the vascular phenotype, we identified the Hspg2 gene that encodes perlecan protein. Perlecan is a proteoglycan heparan sulfate associated with the control of the composition of the extracellular matrix, proliferation of vascular and cartilage cells, and that physically interacts with fibrillin-1 during microfibril and elastic fibers assembly. Thus, in this project we tested the hypothesis that Hspg2 can play a role as a modifier gene of MFS. To this, we measured Hspg2 expression in MFS mice with different genetic backgrounds, evaluating the association between gene expression levels and severity of phenotypes; we obtained RNA-seq data from spinal column from mildly and severely affected mice to analyze the differential expression of other candidate modifier genes, as well as the molecular pathways involved in the disease. Besides that, we generate a SMF mouse model carrying a haploinsufficient mutation in Hspg2 gene as a tool for future investigations about the role of this gene in the SMF physiopathology. We found that animals severely affected for both skeletal and vascular phenotypes showed lower Hspg2 levels and that Hspg2 expression is positively correlated to Fbn1 expression. This suggests that Hspg2 gene can play a protective role in skeletal and vascular phenotypes and highlights the important relation between Fbn1 and Hspg2 in the maintenance of these tissues. The function of Hspg2 in the modulation of MFS phenotypes will be further studied in the new mouse model generated in this work, which will increase our knowledge about the physiopathology of the disease. This in turn may lead to the development of new therapeutic strategies for MFS and other diseases involving the same systems (AU)

• FAPESP's process: 16/18255-3 - Characterization of the role of the Hspg2 gene as a modulator of cardiovascular and skeletal phenotypes in Marfan Syndrome
• Grantee: Isabela Gerdes Gyuricza
• Support Opportunities: Scholarships in Brazil - Master