Analysis of the double heterozygous Hspg2+/- Fbn1+/mg”loxPneo murine model for skeletal and vascular phenotypes variability studies in Marfan Syndrome

• Grant number: 20/15779-7
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): May 01, 2021
• Effective date (End): April 30, 2022
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Glauco de Oliveira Gavioli Ferreira
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Marfan syndrome (MFS) is a hereditary and pleiotropic genetic condition characterized by connective tissue anomalies, of which clinical manifestations occur mainly in the skeletal, cardiovascular and ocular systems. Due to mutations in the FBN1 gene that encodes the fibrilin-1 extracellular matrix glycoprotein, the MFS presents variable expressiveness that results in an large clinical variability even within the same family and without clear genotype-phenotype correlations, which suggests the existence of marfanoid phenotype modifying genes. Linkage experiments conducted in the mg”loxPneo murine model for MFS revealed loci associated with the severity of the skeletal and cardiovascular phenotypes in which the contiguity of two of them, one related to the skeletal (Awtq1) and the other to the cardiovascular phenotype (Krq2), suggests the influence of a common gene in both phenotypes. Hence, the Hspg2 gene that encodes perlecan a heparan sulfate proteoglycan that interacts directly with fibrillin-1 was identified at the Awtq1 locus. Positive correlations were also found between the expressions of Fbn1 and Hspg2 in mg”loxPneo mice from different backgrounds, suggesting the cooperation of these two genes, just as less expression of Hspg2 was observed in those animals with more severe skeletal and cardiovascular phenotypes. Finally, a double heterozygous Hspg2+/- Fbn1+/mg”loxPneo murine model was developed for future studies. Therefore, this project hypothesizes that the low expression of the HSPG2 gene leads to more severe skeletal and vascular phenotypes in MFS, which will be tested by comparing the intensity of these phenotypes between the mg”loxPneo and the Hspg2+/- Fbn1+/mg”loxPneo models. Quantitative analyzes of both phenotypes and the correlation between immunofluorescences and echocardiography will be performed in both groups.