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Identification of novel genes and functional studies in nonsyndromic deafness

Grant number: 14/13071-6
Support type:Regular Research Grants
Duration: August 01, 2014 - January 31, 2017
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Karina Lezirovitz Mandelbaum
Grantee:Karina Lezirovitz Mandelbaum
Home Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Assoc. researchers:Jeanne Oiticica Ramalho Ferraz ; Raquel Salomone ; Regina Célia Mingroni Netto ; Ricardo Ferreira Bento


Genetic mapping of deafness genes in large families lead to the discovery of more than a hundred loci associated with hereditary deafness, including the DFNA58 locus mapped by our team. About 50 gene products were identified since 1990, providing amazing knowledge to the comprehension of auditory physiology. Thus, the task of identifying novel deafness genes is not trivial, remaining an important amount of genes to be discovered and its role in hearing characterized. During the identification and validation of the biological role of novel genes, the contribution of animal models has been remarkable in unrevealing genetic, molecular and physiological aspects of the complex mammal development. These models are also essential to the development of novel therapeutic approaches. This research project aims to identify novel genes in deaf patients and perform functional studies to characterize its role in hearing. The research will be conducted in four branches: 1) Genetic mapping and identification of novel deafness genes by means of linkage analysis and exome sequencing in families already ascertained with non-syndromic deafness, and in families that will be ascertained from the new genetic counseling unit, followed by studies of functional validation of the novel candidate genes. 2) Functional studies of the duplication identified in the DFNA58 locus: Exome sequencing and array-CGH analysis in samples from affected members of the DFNA58 famiy revealed the presence of a ~180Kb duplication within the mapped candidate chromosomal region, that includes two entire genes and partially one more gene. This duplication is not listed CNVs (Copy Number Variation) databases, either the ones that compile variants found in the normal population or that compile variants associated with abnormal phenotypes. Therefore, the aim of this project branch is to determine which of the genes within the duplication are actually responsible for deafness in the DFNA58 family. We plan to achieve this goal through three strategies: a) Characterization of the expression (of mRNA and its proteins) of the three genes in the cochlea of neonatal, young and adult mice.; b) Screen for CNVs of these three genes by MLPA analysis in a cohort of about 50 probands with probably autosomal dominant deafness; c) Characterize the break points with new quantitative real time PCR and arrayCGH experiments to reduce the candidate regions and identify them. d) Develop of a transgenic mice overpexpressing the best candidate gene within the duplication, defined by the results of the previous strategies in order to confirm and characterize the gene role in the deafness etiology. 3) Exome sequencing in patients with monoalellic mutations in the GJB2, SCL26A4 and OTOF genes aiming to search for the second recessive mutation or to identify mutations in other genes that contribute to the phenotype. 4) Restrospective and prospective study of the cochlear implant results regarding the hearing loss etiology, focusing on the molecular diagnosed genetic cases. Since cochlear implant is an invasive and expensive surgical procedure, the identification of factors that may predict its efficiency has important practical implications. As a consequence, the establishment of a routine of molecular-genetic diagnosis in individuals and families with syndromic and non-syndromic deafness, with immediate applications in etiologic diagnosis and genetic counseling for families and that we hope will allow ascertainment of new interesting families for new mapping studies. (AU)