Characterization of the role of the Hspg2 gene as a modulator of cardiovascular and skeletal phenotypes in Marfan syndrome

• Grant number: 16/16077-0
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2016
• End date: November 30, 2019
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Lygia da Veiga Pereira
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Silvia Maria Gomes Massironi

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, excessive growth of bones, scoliosis and chest deformities, lens dislocation and myopia. Despite complete penetrance, MFS has a great clinical variability, which in principle could be explained by different mutations in the FBN1 gene found in different families. Although some types of mutations in FBN1 were associated with more severe phenotypes, no genotype-phenotype relationship has been established that explains the clinical variability in the syndrome. Furthermore, intrafamilial clinical variability, i.e., between individuals with the same mutation, indicates the existence of genes modifying the MFS phenotype in humans. Recently, our group has identified five loci associated with more severe phenotypes (3 loci for the skeletal system, and 2 for the cardiovascular) in an animal model of this syndrome. Among the genes on Awqt1 locus associated with a more severe cardiovascular phenotype, we identified the Hspg2 gene encoding perlecan protein, a proteoglycan heparan sulfate associated with the control of the composition of the extracellular matrix, proliferation of vascular endothelial cells, and that interacts with fibrillin-1 during microfibril formation in the elastic fibers. Thus, in this project we will test the hypothesis that Hspg2 is a modifier gene in MFS. To this, (1) we will measure Hspg2 expression in heterozygous animals Fbn1 (+/-) with different genetic backgrounds, evaluating the association between gene expression levels and severity of phenotypes; (2) we will generate double heterozygous animals Fbn1 (+/-) Hspg2 (+/-), and measure the effect of perlecan haploinsufficiency in the severity of the MFS phenotypes; (3) by RNA-Seq of aorta and femur of animals differently affected, we will analyze if the expression of other candidate modifier genes is associated with more severe phenotypes. The identification of genes involved in modulating the MFS phenotypes will increase our understanding of the basic biology of each system involved in the syndrome and on the metabolic pathways involved in each clinical manifestation. This in turn may lead to the development of new therapeutic strategies for MFS and other diseases involving the same systems. (AU)

Scientific publications

(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, v. 28, n. 9, JUN 2020. (16/16077-0, 18/11708-8, 16/18255-3)