JEANNE DA ROSA OITICICA RAMALHO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/32 - Laboratório de Otorrinolaringologia, Hospital das Clínicas, Faculdade de Medicina
LIM/32 - Laboratório de Otorrinolaringologia, Hospital das Clínicas, Faculdade de Medicina
12 resultados
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- Novel partial duplication of EYA1 causes branchiootic syndrome in a large Brazilian family(2015) DANTAS, Vitor G. L.; FREITAS, Erika L.; DELLA-ROSA, Valter A.; LEZIROVITZ, Karina; MORAES, Ana Maria S. M. de; RAMOS, Silvia B.; OITICICA, Jeanne; ALVES, Leandro U.; PEARSON, Peter L.; ROSENBERG, Carla; MINGRONI-NETTO, Regina C.Objective: To identify novel genetic causes of syndromic hearing loss in Brazil. Design: To map a candidate chromosomal region through linkage studies in an extensive Brazilian family and identify novel pathogenic variants using sequencing and array-CGH. Study sample: Brazilian pedigree with individuals affected by BO syndrome characterized by deafness and malformations of outer, middle and inner ear, auricular and cervical fistulae, but no renal abnormalities. Results: Whole genome microarray-SNP scanning on samples of 11 affected individuals detected a multipoint Lod score of 2.6 in the EYA1 gene region (chromosome 8). Sequencing of EYA1 in affected patients did not reveal pathogenic mutations. However, oligonucleotide-array-CGH detected a duplication of 71.8Kb involving exons 4 to 10 of EYA1 (heterozygous state). Real-time-PCR confirmed the duplication in fourteen of fifteen affected individuals and absence in 13 unaffected individuals. The exception involved a consanguineous parentage and was assumed to involve a different genetic mechanism. Conclusions: Our findings implicate this EYA1 partial duplication segregating with BO phenotype in a Brazilian pedigree and is the first description of a large duplication leading to the BOR/BO syndrome.
- Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss(2022) BATISSOCO, Ana Carla; PEDROSO-CAMPOS, Vinicius; PARDONO, Eliete; SAMPAIO-SILVA, Juliana; SONODA, Cindy Yukimi; VIEIRA-SILVA, Gleiciele Alice; LONGATI, Estefany Uchoa da Silva de Oliveira; MARIANO, Diego; HOSHINO, Ana Cristina Hiromi; TSUJI, Robinson Koji; JESUS-SANTOS, Rafaela; ABATH-NETO, Osorio; BENTO, Ricardo Ferreira; OITICICA, Jeanne; LEZIROVITZ, KarinaHearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in similar to 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.
- Hearing aid effectiveness on patients with chronic tinnitus and associated hearing loss(2022) SIMONETTI, Patricia; VASCONCELOS, Laura Garcia; GÂNDARA, Mara Rocha; LEZIROVITZ, Karina; MEDEIROS, Ítalo Roberto Torres de; OITICICA, JeanneAbstract Objective: Our study aimed to measure the effectiveness of using HA in reducing the disturbance caused by tinnitus. Methods: Study was designed as a within-subjects clinical trial. Nineteen patients with chronic tinnitus and untreated sensorineural hearing loss were under counseling, HA fitting and 6 months follow-up. Tinnitus assessment was performed with Tinnitus Handicap Inventory (THI), Visual Analog Scale (VAS), pitch and loudness matching, and Minimum Masking Level measurements (MML). Results: following 6 months of HA use, a reduction in reported tinnitus and hearing handicap scales scores was observed both statistically and clinically. The pitch and loudness matching, as well as MML at the baseline and final evaluation were compared. MML’s thresholds reduced significantly after 6 months of HA use. Conclusion: Our study has provided evidence that HA fitting is a valuable treatment strategy for chronic tinnitus relief and associated hearing loss subtype of patient. Level of evidence: 3.
- Cochlea cell-specific marker expression upon in vitro Hes1 knockdown(2021) BATISSOCO, A. C.; LEZIROVITZ, K.; ZANATTA, D. B.; HEMZA, C. R. M. L.; VASQUES, L. R.; STRAUSS, B. E.; MINGRONI-NETTO, R. C.; HADDAD, L. A.; BENTO, R. F.; OITICICA, J.NOTCH pathway proteins, including the transcriptional factor HES1, play crucial roles in the development of the inner ear by means of the lateral inhibition mechanism, in which supporting cells have their phenotype preserved while they are prevented from becoming hair cells. Genetic manipulation of this pathway has been demonstrated to increase hair cell number. The present study aimed to investigate gene expression effects in hair cells and supporting cells after Hes1-shRNA lentivirus transduction in organotypic cultures of the organ of Corti from postnatal-day-3 mice. Forty-eight hours after in vitro knockdown, Hes1 gene expression was reduced at both mRNA and protein levels. Myo7a (hair cell marker) and Sox2 (progenitor cell marker) mRNA levels also significantly increased. The modulation of gene expression in the organ of Corti upon Hes1 knockdown is consistent with cell phenotypes related to lateral inhibition mechanism interference in the inner ear. The lentivirus-based expression of Hes1-sh RNA is a valuable strategy for genetic interference in the organ of Corti and for future evaluation of its efficacy in protocols aiming at the regeneration of hair cells in vivo.
bookPart Etiologia da Deficiência Auditiva(2014) OITICICA, Jeanne; LEZIROVITZ, Karina; BATISSOCO, Ana Carla- A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58(2020) LEZIROVITZ, Karina; VIEIRA-SILVA, Gleiciele A.; BATISSOCO, Ana C.; LEVY, Debora; KITAJIMA, Joao P.; TROUILLET, Alix; OUYANG, Ellen; ZEBARJADI, Navid; SAMPAIO-SILVA, Juliana; PEDROSO-CAMPOS, Vinicius; NASCIMENTO, Larissa R.; SONODA, Cindy Y.; BORGES, Vinicius M.; VASCONCELOS, Laura G.; BECK, Roberto M. O.; GRASEL, Signe S.; JAGGER, Daniel J.; GRILLET, Nicolas; BENTO, Ricardo F.; MINGRONI-NETTO, Regina C.; OITICICA, JeanneHere we define a similar to 200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.
bookPart Surdez Neonatal de Origem Genética(2014) OITICICA, Jeanne; LEZIROVITZ, Karina; BATISSOCO, Ana Carla- Evidence of progenitor cells in the adult human cochlea: sphere formation and identification of ABCG2(2017) MASSUCCI-BISSOLI, Milene; LEZIROVITZ, Karina; OITICICA, Jeanne; BENTO, Ricardo FerreiraOBJECTIVES: The aim of this study was to search for evidence of stem or progenitor cells in the adult human cochlea by testing for sphere formation capacity and the presence of the stem cell marker ABCG2. METHODS: Cochleas removed from patients undergoing vestibular schwannoma resection (n=2) and from brain-dead organ donors (n=4) were dissociated for either flow cytometry analysis for the stem cell marker ABCG2 or a sphere formation assay that is widely used to test the sphere-forming capacity of cells from mouse inner ear tissue. RESULTS: Spheres were identified after 2-5 days in vitro, and the stem cell marker ABCG2 was detected using flow cytometric analysis after cochlear dissociation. CONCLUSIONS: Evidence suggests that there may be progenitor cells in the adult human cochlea, although further studies are required.
- Exome Sequencing Identifies a Novel Nonsense Mutation of MYO6 as the Cause of Deafness in a Brazilian Family(2018) SAMPAIO-SILVA, Juliana; BATISSOCO, Ana Carla; JESUS-SANTOS, Rafaela; ABATH-NETO, Osorio; SCARPELLI, Luciano Cesar; NISHIMURA, Patricia Yoshie; GALINDO, Layla Testa; BENTO, Ricardo Ferreira; OITICICA, Jeanne; LEZIROVITZ, KarinaWe investigated 313 unrelated subjects who presented with hearing loss to identify the novel genetic causes of this condition in Brazil. Causative GJB2/GJB6 mutations were found in 12.7% of the patients. Among the familial cases (100/313), four were selected for exome sequencing. In one case, two novel heterozygous variants were found and were predicted to be pathogenic based on bioinformatics tools, that is, p.Ser906* (MYO6) and p.Arg42Cys (GJB3). We confirmed that this nonsense MYO6 mutation segregated with deafness in this family. Only the proband and her unaffected mother exhibited the GJB3 mutation, which is in the same amino acid of a known Erythrokeratodermia variabilis mutation. None of the patients exhibited this skin disease, but the proband exhibited a more severe hearing loss. Hence, the GJB3 mutation was considered to be a variant of uncertain significance. In conclusion, we described a novel nonsense MYO6 mutation that was responsible for the hearing loss in a Brazilian family. This mutation resides in the neck domain of myosin-VI after the motor domain. Thus, our data give further support for genotype-phenotype correlations, which state that when the motor domain of the protein is functioning, the hearing loss is milder and has a later onset. The three remaining families without mutations in the known genes suggest that there are still deafness genes to be revealed.
- Transplantation and survival of mouse inner ear progenitor/stem cells in the organ of Corti after cochleostomy of hearing-impaired guinea pigs: preliminary results(2016) BARBOZA JR., L. C. M.; LEZIROVITZ, K.; ZANATTA, D. B.; STRAUSS, B. E.; MINGRONI-NETTO, R. C.; OITICICA, J.; HADDAD, L. A.; BENTO, R. F.In mammals, damage to sensory receptor cells (hair cells) of the inner ear results in permanent sensorineural hearing loss. Here, we investigated whether postnatal mouse inner ear progenitor/stem cells (mIESCs) are viable after transplantation into the basal turns of neomycin-injured guinea pig cochleas. We also examined the effects of mIESC transplantation on auditory functions. Eight adult female Cavia porcellus guinea pigs (250-350g) were deafened by intratympanic neomycin delivery. After 7 days, the animals were randomly divided in two groups. The study group (n = 4) received transplantation of LacZ-positive mIESCs in culture medium into the scala tympani. The control group (n = 4) received culture medium only. At 2 weeks after transplantation, functional analyses were performed by auditory brainstem response measurement, and the animals were sacrificed. The presence of mIESCs was evaluated by immunohistochemistry of sections of the cochlea from the study group. Non-parametric tests were used for statistical analysis of the data. Intratympanic neomycin delivery damaged hair cells and increased auditory thresholds prior to cell transplantation. There were no significant differences between auditory brainstem thresholds before and after transplantation in individual guinea pigs. Some mIESCs were observed in all scalae of the basal turns of the injured cochleas, and a proportion of these cells expressed the hair cell marker myosin VIIa. Some transplanted mIESCs engrafted in the cochlear basilar membrane. Our study demonstrates that transplanted cells survived and engrafted in the organ of Corti after cochleostomy.