Establishment and characterisation of a new murine model for Marfan syndrome studies: mg”loxP

• Grant number: 15/12446-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): August 01, 2015
• Effective date (End): July 31, 2016
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Carolina de Athayde Mendonça
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The Marfan syndrome (MFS) is a genetic disease that affects the connective tissue, exhibiting extreme pleiotropism and clinical variability. The most affected systems are: ocular, cardiovascular and skeletal. The disease is caused by mutations in the gene that encodes Fibrilin-1 (Fbn1), which is an important component of the extracellular matrix. In 1997, a first murine model was developed by replacing the exons 19-24 of the Fbn1 gene with a cassette of resistance to neomycin (neo): the strain mg”. Analyses of the animals revealed that the expression of the mutated allele was extremely reduced when compared to the wild allele. These results are not in accordance with the model of negative dominance proposed to the SMF, in which the altered fibrinllin would be expressed in high levels and interfere in the stabilization of the microfibrils. Probably, the reduced expression is caused by the presence of the neo gene that could interfere in the expression of the sequence in which it was inserted. The Cre/Lox-P recombination system is an efficient method to remove resistance genes of genetic manipulated animals. Being so, a new model was developed (the mg”loxPneo) in which the neo gene was flanked by Lox-P sequences. If this strain is crossed with one that expresses the Cre-recombinase, the cassette can be removed and, as a consequence, the expression of the allele may increase. The present work aims at establishing and characterizing, genotipically and phenotipically, this new strain: mg”loxP.