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Functional analysis of FBN1 mutations in human Pluripotent Stem-Cells (hPSCs)

Grant number: 16/16076-4
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2016
Effective date (End): October 31, 2020
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
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
Associated scholarship(s):17/17186-0 - Unveiling mechanisms of Marfan Syndrome-related cardiomyopathy, BE.EP.DD


The FBN1 gene encodes the extracellular matrix protein fibrillin-1, the major structural component of the microfibrils that form the elastic fibers. Mutations in this gene were related to the occurrence of Marfan Syndrome (MFS), an autosomal dominant connective tissue disorder whose clinical manifestations include Dilated Cardiomyopathy (DCM), bone overgrowth and thoracic deformities. More than 3000 mutations have been described for the syndrome, yet there are no well-established genotype-phenotype correlations, with few exceptions. Fibrillin-1 is important in the modulation of the bioavailability of the Transforming Growth Factor-beta (TGF-beta) during osteogenesis. In vitro, MFS human Pluripotent Stem-Cells (hPSCs) show absence of osteogenic differenciation when compared to wild-type cells, and this phenotype is reversed by TGF-beta signaling inhibition. In a mouse model for fibrillin-1 haploinsufficiency, it was observed that the occurrence of DCM, present in less than 25% of MFS patients, is a primary consequence of the syndrome, and not secondary as thought before. In vitro, cardiomyocytes derived from patients with familial forms of DCM (not related to MFS) show structural and physiological differences when compared to healthy cells, including sarcomeric disorganization and a pronounced punctate distribution of sarcomeric alpha-actinin. CRISPR/Cas9 is a system used as a genome editing tool that allows the engineering of mutant molecular models from wild-type ones, which leads to the generation of isogenic lineages that facilitate the study of the effects of particular mutations in a gene. Considering this information, the aim of this project is to generate FBN1 mutant hPSCs using CRISPR/Cas9 system to analyze the effects of haploinsufficiency or dominant-negative mutations of/in fibrillin-1 during osteogenic differentiation and also in in vitro generated cardiomyocytes to, perhaps, establish new genotype-phenotype correlations for Marfan Syndrome. (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)
SARAFIAN, RAQUEL; MORATO-MARQUES, MARIANA; BORSOI, JULIANA; PEREIRA, LYGIA VEIGA. Monitoring cell line identity in collections of human induced pluripotent stem cells. STEM CELL RESEARCH, v. 28, p. 66-70, . (16/16076-4, 16/20650-8, 13/08135-2)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SANT'ANA, Juliana Borsoi. A human pluripotent stem cell model to study the haploinsufficiency and dominant negative molecular mechanisms of Marfan Syndrome. 2020. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) São Paulo.

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