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Epigenetic analysis of the phenotypic variability of a mouse model for Marfan syndrome

Grant number: 21/09203-8
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): June 01, 2022
Effective date (End): March 31, 2023
Field of knowledge:Interdisciplinary Subjects
Principal Investigator:Lygia da Veiga Pereira
Grantee:Rayssa de Carvalho Roberto
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Marfan Syndrome (MFS) is an autosomal dominant genetic condition, with complete penetrance, inter and intra-family clinical variability. It has an incidence of 1 in approximately 5,000 individuals, around 25% of these cases are sporadic. The systems most affected by the syndrome are ocular, cardiovascular and skeletal. MFS is caused by pathogenic variants in the FBN1 gene, which encodes the fibrilin-1 extracellular matrix protein, the main structural component of the microfibrils, that are part of the elastic (which provides structural support and elasticity) and non-elastic (which provides anchorage) tissues. More than 3,000 pathogenic variants have already been identified, but establish a genotype-phenotype correlation is still a defiance, so that few correlations are established. Two molecular mechanisms can explain the occurrence of MFS: negative dominant (DN), where mutants and normal monomers are used to form microfibrils; and haploinsufficiency (HI), where the amount of protein produced by the normal FBN1 allele is not sufficient for the correct formation of microfibrils. Phenotypic differences between these mechanisms have been reported, but due to the likely contribution of modifying genes (caused by differences in the genetic background between different individuals), the pathogenesis mechanism of the different variants is still unclear. The mg”neoLoxP animal model presents skeletal, cardiovascular, and pulmonary manifestations for MFS, in addition to the clinical variability of the syndrome observed in humans. The model was established in the 129/Sv and C57BL/6 isogenic strains. Phenotypic differences observed between 129/Sv isogenic animals suggest that epigenetic changes may be related to the variability of the clinical manifestations. Thus, this work aims to verify the existence of epigenetic changes in the Fbn1 gene among animals with severe and mild phenotypes, analyzing the methylation of the Fbn1 CpG island and verify other epigenetic changes along the genome that may be related to the clinical variability found in 129/Sv animals.

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