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Generation of FBN1 gene mutations in Induced Pluripotent Stem Cells (IPSCs) using CRISPR/Cas9 system

Grant number: 15/01339-7
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): May 01, 2015
Effective date (End): October 31, 2016
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Lygia da Veiga Pereira
Grantee:Juliana Borsoi Sant'Ana
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


FBN1 gene encodes the extracellular matrix protein fibrillin-1, the major structural component of the microfibrils that comprise the elastic fibers. Mutations in this gene were related to the occurrence of Marfan Syndrome (MFS), an autossomal dominant connective tissue disorder that causes many clinical manifestations such as bone overgrowth, scoliosis and thoracic deformities. Fibrillin-1 is important in the modulation of the bioavailability of the Transforming Growth Factor beta (TGF-beta) during osteogenesis. In vitro, MFS iPSCs show absence of osteogenic differenciation when compared to wild-type cells, and this phenotype is reversed by TGF-beta signalling inhibition. In our laboratory, inhibition of osteogenesis was observed in conditions of low cellular density in both MFS and wild-type iPSCs, demonstrating that the proliferation rate of each lineage could be determinant in the process. CRISPR/Cas9 system is a prokaryotic genetic immune system used as a DNA targeted edition tool. The engineering of molecular mutant models from wild-type models, yielding isogenic lineages, eliminates many variables and facilitates the study of gene functions. With these observations in mind, the aim of this project is the generation of FBN1 mutant iPSCs using CRISPR/Cas9 system, and posterior validation of these models by comparing them, during osteogenic differentiation, with iPSCs derived from MFS patients. (AU)

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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)
BORSOI, JULIANA; MORATO-MARQUES, MARIANA; TOFOLI, FABIANO DE ARAUJO; PEREIRA, LUCAS ASSIS; FARINHA-ARCIERI, LUIS ERNESTO; SARAFIAN, RAQUEL DELGADO; PEREZ, ANA BEATRIZ ALVAREZ; PEREIRA, LYGIA VEIGA. Generation of two human induced pluripotent stem cell (hiPSC) lines derived from unrelated Marfan Syndrome patients. STEM CELL RESEARCH, v. 54, p. 5-pg., . (15/01339-7)
BORSOI, JULIANA; FARINHA-ARCIERI, LUIS ERNESTO; MORATO-MARQUES, MARIANA; SARAFIAN, RAQUEL DELGADO; PINHEIRO, MARA; PEREIRA, LYGIA VEIGA. Generation of genetically modified human induced pluripotent stem cell lines harboring haploin sufficient or dominant negative variants in the FBN1 gene. STEM CELL RESEARCH, v. 54, . (15/01339-7)

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