Karina Lezirovitz

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

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Regina Célia Mingroni‐Netto

Universidade de São Paulo

Ana Carla Batissoco

Universidade de São Paulo

Jeanne Oiticica

Universidade de São Paulo

Paulo Alberto Otto

Universidade de São Paulo

Ricardo Ferreira Bento

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Fernando Kok

Mendelics

Ronaldo Serafim Abreu-Silva

Universidade de São Paulo

Eliete Pardono

Universidade Paulista

Luciana A. Haddad

Universidade de São Paulo

Sulene Pirana

Universidade de São Paulo

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Universidade de São Paulo

121

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Instituto Biológico

Universidade Federal de São Paulo

Universidade Brasil

Hospital Universitário da Universidade de São Paulo

University of Göttingen

Pontifícia Universidade Católica de São Paulo

Universitätsmedizin Göttingen

Universidade Estadual de Campinas (UNICAMP)

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Novel partial duplication ofEYA1causes branchiootic syndrome in a large Brazilian family

International Journal of Audiology (2015)

Vitor G.L. Dantas Érika L. Freitas Valter Augusto Della-Rosa Karina Lezirovitz Ana Maria Silveira Machado de Moraes

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.

SNP array

Candidate gene

Segmental duplication

10.3109/14992027.2015.1030511

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Citations (8)

Mapeamento de locos responsáveis por surdez não-sindrômica em famílias brasileiras

Karina Lezirovitz Maria Cristina C. Braga Paulo Alberto Otto Regina Célia Mingroni‐Netto

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Frequency and origin of the c.2090T>G p.(Leu697Trp) MYO3A variant associated with autosomal dominant hearing loss

European Journal of Human Genetics (2021)

André Silva Bueno Kelly Nunes Alex Marcel Moreira Dias Leandro Ucela Alves Beatriz de Castro Andrade Mendes

10.1038/s41431-021-00891-0

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Citations (10)

Syndromic hearing loss molecular diagnosis: Application of massive parallel sequencing

Hearing Research (2018)

Yasmin Soares de Lima Marcela A. Chiabai Jun Shen Mara S. Córdoba Beatriz R. Versiani

Etiology

Treacher Collins Syndrome

Clinical Diagnosis

10.1016/j.heares.2018.10.008

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Transplantation and survival of mouse inner ear progenitor/stem cells in the organ of Corti after cochleostomy of hearing-impaired guinea pigs: preliminary results

Brazilian Journal of Medical and Biological Research (2016)

Luiz Carlos M. Barboza Karina Lezirovitz Daniela B. Zanatta Bryan E. Strauss Regina Célia Mingroni‐Netto

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.

Auditory brainstem response

Basilar membrane

Cavia

10.1590/1414-431x20155064

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Citations (13)

Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness

European Journal of Human Genetics (2007)

Karina Lezirovitz Eliete Pardono Maria Teresa Balester De Mello Auricchio Fernando L de Carvalho e Silva Juliana J Lopes

Pedigree chart

Locus heterogeneity

Allelic heterogeneity

Genetic linkage

10.1038/sj.ejhg.5201917

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Citations (60)

c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family

Genetics and Molecular Biology (2014)

Vitor G.L. Dantas Karina Lezirovitz Guilherme Lopes Yamamoto Carolina Fischinger Moura de Souza Simone Gomes Ferreira

We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR - c.G894A:p.R298R and PTGER2 - c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family.

Candidate gene

Genetic linkage

Exome

10.1590/s1415-47572014005000025

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Citations (9)

Polyethylene Glycol fusion associated with anti‐oxidants: A new promise in the treatment of traumatic paralysis

Head & Neck (2018)

Raquel Salomone Alfredo Luiz Jácomo Ricardo Ferreira Bento Silvia Nascimento Karina Lezirovitz

Contrary to what is described in our article1, Bittner et al.2 and Bamba et al.3 evaluated the composite action potential (CAP), instead of composite muscular action potential (CMAP). The correct legend of Figure 1 is: Figure showing the steps of the PEG-fusion experience: A- Surgical preparation of stumps following by bathing the stumps in a hypotonic Ca2 -free Krebs physiological saline and bath the stumps with methylene blue (MB) in hypotonic Ca2+-free saline for 3 minutes. B- Microsuture. C- Bathing the nerve in a hypotonic Ca+2 free PEG solution (double distilled H2O) for 2 minutes D- Bathing the nerve in isotonic Ca+2 containing (Krebs) for 3 minutes. The method was not fully described in the article, so for a better accuracy and reproducibility, we supplement the information with the following: PEG-fusion was carried out bathing the stumps in hypotonic Ca + 2 free Krebs physiological saline (0,5 mM EGTA, 99 mM NaCl, 5 mM KCl, 1,2 Mm KH2PO4, 1,3 mM MgSO4, 26 mM NaHCO3, 10 mM sodium ascorbate, 10 mM dextrose, pH 7,35 in 319 mOsm double distilled H2O); 100 μM methylene blue in hypotonic Ca2 + −free saline for 3 minutes (Figure 1A), prior to the sutures. After sutures (Figure 1B), the resulting nerve was bathed in a 500 mM PEG solution dissolved in double distilled H2O for two minutes (Figure 1C). Last, isotonic Ca + 2 containing Krebs saline was applied to the nerve for 3 min (Figure 1E). PEG average molecular weight used was 200 Da. Due to the use of PEG with average molecular weight of 200 Da, the method used would be better referred as "PEG-Fusion experience", since the so-called "PEG-Fusion protocol" described by Bittner et al. (2012) used a 2 k Da molecular weight of PEG. There are recently published papers describing that the molecular weight of PEG may interfere with the results. The authors would like to apologize for any inconvenience caused.

Distilled water

Methylene blue

10.1002/hed.25626

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Prevalence of GJB2 (Connexin-26) and GJB6 (Connexin-30) Mutations in a Cohort of 300 Brazilian Hearing-Impaired Individuals: Implications for Diagnosis and Genetic Counseling

Ear and Hearing (2008)

Ana Carla Batissoco Ronaldo Serafim Abreu-Silva Maria Cristina C. Braga Karina Lezirovitz Valter Augusto Della-Rosa

Hereditary nonsyndromic deafness is an autosomal recessive condition in about 80% of cases, and point mutations in the GJB2 gene (connexin 26) and two deletions in the GJB6 gene (connexin 30), del(GJB6-D13S1830) and del(GJB6-D13S1854), are reported to account for 50% of recessive deafness. Aiming at establishing the frequencies of GJB2 mutations and GJB6 deletions in the Brazilian population, we screened 300 unrelated individuals with hearing impairment, who were not affected by known deafness related syndromes.We firstly screened the most frequently reported mutations, c.35delG and c.167delT in the GJB2 gene, and del(GJB6-D13S1830) and del(GJB6-D13S1854) in the GJB6 gene, through specific techniques. The detected c.35delG and c.167delT mutations were validated by sequencing. Other mutations in the GJB2 gene were screened by single-strand conformation polymorphism and the coding region was sequenced when abnormal patterns were found.Pathogenic mutations in GJB2 and GJB6 genes were detected in 41 individuals (13.7%), and 80.5% (33/41) presented these mutations in homozygosis or compound heterozygosis, thus explaining their hearing defect. The c.35delG in the GJB2 gene was the most frequent mutation (37/300; 12.4%), detected in 23% familial and 6.2% the sporadic cases. The second most frequent mutation (1%; 3/300) was the del(GJB6-D13S1830), always found associated with the c.35delG mutation. Nineteen different sequence variations were found in the GJB2 gene. In addition to the c.35delG mutation, nine known pathogenic alterations were detected c.167delT, p.Trp24X, p.Val37Ile, c.176_191del16, c.235delC, p.Leu90Pro, p.Arg127His, c.509insA, and p.Arg184Pro. Five substitutions had been previously considered benign polymorphisms: c.-15C>T, p.Val27Ile, p.Met34Thr, p.Ala40Ala, and p.Gly160Ser. Two previously reported mutations of unknown pathogenicity were found (p.Lys168Arg, and c.684C>A), and two novel substitutions, p.Leu81Val (c.G241C) and p.Met195Val (c.A583G), both in heterozygosis without an accompanying mutation in the other allele. None of these latter four variants of undefined status was present in a sample of 100 hearing controls.The present study demonstrates that mutations in the GJB2 gene and del(GJB6 D13S1830) are important causes of hearing impairment in Brazil, thus justifying their screening in a routine basis. The diversity of variants in our sample reflects the ethnic heterogeneity of the Brazilian population.

10.1097/aud.0b013e31819144ad

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Citations (91)

Spastic Paraplegia, Optic Atrophy, and Neuropathy: New Observations, Locus Refinement, and Exclusion of Candidate Genes

Annals of Human Genetics (2009)

Lúcia Inês Macedo‐Souza Fernando Kok Silvana Santos Luciana Licínio Karina Lezirovitz

Summary SPOAN is an autosomal recessive neurodegenerative disorder which was recently characterized by our group in a large inbred Brazilian family with 25 affected individuals. This condition is clinically defined by: 1. congenital optic atrophy; 2. progressive spastic paraplegia with onset in infancy; and 3. progressive motor and sensory axonal neuropathy. Overall, we are now aware of 68 SPOAN patients (45 females and 23 males, with age ranging from 5 to 72 years), 44 of which are presented here for the first time. They were all born in the same geographic micro region. Those 68 patients belong to 43 sibships, 40 of which exhibit parental consanguinity. Sixty‐one patients were fully clinically evaluated and 64 were included in the genetic investigation. All molecularly studied patients are homozygotes for D11S1889 at 11q13. This enabled us to reduce the critical region for the SPOAN gene from 4.8 to 2.3 Mb, with a maximum two point lod score of 33.2 (with marker D11S987) and of 27.0 (with marker D11S1889). Three genes located in this newly defined critical region were sequenced, but no pathogenic mutation was detected. The gene responsible for SPOAN remains elusive.

Paraplegia

Candidate gene

10.1111/j.1469-1809.2009.00507.x

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Citations (44)