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Investigation of new hereditary forms of hearing loss and its pathophysiological mechanism

Abstract

The sense of hearing is crucial for human interaction with the environment and its dysfunction orloss can have a lifelong social, financial, vocational, and educational impact. Deafness, hearing loss (HL), orimpairment, is one of the most heterogeneous disorders known. It presents vast clinical (syndromic and nonsyndromic)and etiological heterogeneity, as only for the non-syndromic forms there are more than 180candidate chromosomal regions that have already been mapped in studies carried out in differentpopulations. Despite this, only 136 of these genes have been identified, which illustrates the arduous task ofidentifying hearing loss genes. Clinically similar forms can be caused by different genes, while differentvariants in the same gene can lead to different clinical conditions, syndromic or not, and even with differentinheritance patterns. Each genetic form of hearing loss is individually rare and presents clinical peculiarities,genotype-phenotype relationships, and pathophysiology, thus revealing the biological pathways subject totherapeutic intervention. The Brazilian population has an enormous potential to discover new genotypephenotyperelationships and reveal new biological pathways fundamental to hearing. Mapping studies,discovery of new genes, and functional studies are only possible in laboratories that have collections ofsamples from interesting and clinically well-studied families, as is the case in our laboratory, with more than500 cases clinically evaluated and whose cause in approximately 80% of them, possibly genetic, still requiresinvestigation. Especially with regard to hearing loss whose human tissue is inaccessible and animal modelsdo not always recapitulate the pathogenic variant and/or form of hearing loss, cellular models derived frompatients' own cells show great promise in meeting the demand for understanding the pathophysiology anddevelop new ways to treat hearing loss. In the last FAPESP grant, we established four iPSC lines from cellsfrom affected and normal-hearing subjects of the DFNA58 family, whose genomic signature, a genomicduplication, was also described in a previous grant. There are many familial cases with genes to be revealedamong those in our series and for which iPSC models would be of great value in the study of hearing loss.This research project aims to map which genes, already known or not, contribute to hearing loss in Brazil,establish genotype-phenotype correlations, and characterize pathophysiological mechanisms in order toguide which genes should be present in gene panels, as well as which biological pathways should receivemore attention for the development of therapeutic interventions. Thus, the research will be carried outthrough three aspects: 1) Mapping the genes related to the pathophysiology of hearing in Brazil, as well asnew variants and genotype-phenotype relationships, through NGS and exome panels, as well as exploringdifferent strategies to search for variants not always detectable by these NGS techniques. 2) Study usingmass spectrometry, differentially expressed proteins from murine cochleae in different pathophysiologicalconditions. 3) Build cellular models based on the induction of pluripotency in cells from patients with hearingloss, through the differentiation of this iPSC into types of auditory cells, characterizing the phenotypic andgene expression differences of iPSC obtained from the blood of patients with genetic hearing loss in relation2to iPSC of hearing individuals (controls), not only for the DFNA58 model, but for the study of new variantsand genes that we identify, not only related to this study but also to other projects developed at LIM32. (AU)

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