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Molecular and functional study of Usher's syndrome using massive sequencing, zebrafish and CRISPR/Cas9 system

Grant number: 17/12798-8
Support Opportunities:Regular Research Grants
Duration: November 01, 2017 - January 31, 2020
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Edi Lúcia Sartorato
Grantee:Edi Lúcia Sartorato
Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Usher syndrome is an autosomal recessive hereditary disease characterized by hearing loss and progressive loss of vision. Vision loss occurs due to retinitis pigmentosa, a degenerative retinal disease that usually appears in adolescence or early adulthood. A global molecular diagnostic protocol for Usher's syndrome has been difficult because of the high genetic heterogeneity, large number of exons of each gene to be analyzed, and the high costs associated with the application of conventional techniques. Therefore, the developed of high performance technologies are needed to facilitate detection of the gene and mutations involved, provide the prevalence of the mutations in the population, as a complement to the clinical diagnosis and prognosis in Neonatal hearing screening. It is important to note that, to date, there is no data in the literature involving a large study of genes associated with Usher's syndrome in Brazilian patients. Thus, in this study we intend to identify the changes involved in Usher Syndrome and the functional consequences of these changes through the following strategies: 1 - Initially use of high-througput technique (whole exome) to identify genes and mutations; 2 - Validation of the phenotype using in vivo study in zebrafish by knock-in with the CRIPR / cas9 system to observe the consequences of changes in the phenotype of these animals. The alterations found will also be analyzed in order to understand the origin and distribution of these mutations in the Brazilian population. Thus, we intend to analyze the ancestry of individuals defining the ethnic components in the genomes of the individuals with these mutations; To evaluate indexes of identity by descent between pairs of individuals and to locate the genomic segments of extended homozygosity; Eventually estimating the age of mutations, the time in generations of the most recent common ancestor of a given mutation, evidently the latter item will be conditioned to the findings of the project. The results will contribute to the elucidation of cases of unknown etiology, early identification of families at risk and optimization of molecular diagnostic tests for hearing loss screening in deaf Brazilian individuals with suspected Usher for better prognosis, treatment and genetic counseling. To understand the genetic basis of this condition. (AU)

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