Karina Lezirovitz

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

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Co-Authors

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

Cooperative Institutions

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 OTOF mutations in Brazilian patients with auditory neuropathy

Journal of Human Genetics (2009)

Jihane Romanos Lilian Kimura Mariana Lopes Fávero Fernanda Attanasio R Izarra Maria Teresa Balester De Mello Auricchio

Proband

Auditory neuropathy

10.1038/jhg.2009.45

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Citations (62)

MSX2 copy number increase and craniosynostosis: copy number variation detected by array comparative genomic hybridization

Clinics (2012)

Karla de Oliveira Pelegrino Sofia M. M. Sugayama Karina Lezirovitz Ana Lúcia Catelani Fernando Kok

Craniosynostosis is a disorder characterized by the premature fusion of the calvarial sutures, causing an abnormal skull shape. Because this disorder occurs with a relatively high frequency, estimated at 1 in 2500 individuals, craniosynostosis represents a relevant medical problem (1). More than 100 syndromes have been shown to be associated with this disorder. It is believed that at least 20% of cases are due to single gene mutations or chromosome abnormalities (2). Although most cases can be considered both clinically and genetically heterogeneous, there is evidence that six genes are involved in many cases: MSX2, FGFR1, FGFR2, FGFR3, FBN1, and TWISTY (1). The Msh homeobox 2 (Msx2) gene encodes a homeodomain transcription factor protein and is expressed in migrating cranial neural crest cells during development (3). Msx2 has central roles in craniofacial development (4) and limb and tissue formation (6). Furthermore, Msx2 overexpression was demonstrated to be associated with craniosynostosis in mice (5,7), indicating that normal craniofacial formation is dependent on the Msx2 dosage. Corroborating these findings, increases in the copy number in the MSX2 region have been reported in craniosynostosis patients (8-11). In the present study, we describe the findings from a whole-genome array comparative genomic hybridization (aCGH) analysis of a four-year-old patient exhibiting craniosynostosis, microcephaly, psychomotor development delay, short stature, and cognitive impairment, among other abnormalities. We found a gain in a region of chromosome 5q35.2 that contains MSX2 and has been shown to be associated with craniosynostosis. Quantitative PCR confirmed the increase in the MSX2 copy number.

Comparative genomic hybridization

Copy number analysis

Gene dosage

Variation (astronomy)

10.6061/clinics/2012(08)23

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Citations (8)

7q36 deletion and 9p22 duplication: effects of a double imbalance

Molecular Cytogenetics (2013)

Karla de Oliveira Pelegrino Sofia M. M. Sugayama Ana Lúcia Catelani Karina Lezirovitz Fernando Kok

Abstract The etiology of mental retardation/developmental delay (MRDD) remains a challenge to geneticists and clinicians and can be correlated to environmental and genetic factors. Chromosomal aberrations are common causes of moderate to severe mental retardation and may represent 10% of these occurrences. Here we report the case of a boy with development delay, hypoplasia of corpus callosum, microcephaly, muscular hypotonia, and facial dysmorphisms. A deletion of 7q36.1 → 36.3 and duplication of 9p22.3 → 23 was detected as a result of an unbalanced translocation of paternal origin. Breakpoint delimitation was achieved with array comparative genomic hybridization assay. Additional multiplex ligation dependent probe amplification (MLPA) analyzes confirmed one copy loss of 7q36.3 region and one copy gain of 9p24.3 region. Patient resultant phenotype is consistent with the already described findings for both 7q deletion and 9p duplication syndromes.

Microcephaly

Comparative genomic hybridization

Breakpoint

10.1186/1755-8166-6-2

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Citations (8)

Duplications ofBHLHA9are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

Journal of Medical Genetics (2011)

Eva Klopocki Silke B. Lohan Sandra C. Doelken Sigmar Stricker Charlotte W. Ockeloen

Background

Split-hand/foot malformation (SHFM)—also known as ectrodactyly—is a congenital disorder characterised by severe malformations of the distal limbs affecting the central rays of hands and/or feet. A distinct entity termed SHFLD presents with SHFM and long bone deficiency. Mouse models suggest that a defect of the central apical ectodermal ridge leads to the phenotype. Although six different loci/mutations (SHFM1–6) have been associated with SHFM, the underlying cause in a large number of cases is still unresolved.

Methods

High resolution array comparative genomic hybridisation (CGH) was performed in patients with SHFLD to detect copy number changes. Candidate genes were further evaluated for expression and function during limb development by whole mount in situ hybridisation and morpholino knock-down experiments.

Results

Array CGH showed microduplications on chromosome 17p13.3, a locus previously associated with SHFLD. Detailed analysis of 17 families revealed that this copy number variation serves as a susceptibility factor for a highly variable phenotype with reduced penetrance, particularly in females. Compared to other known causes for SHFLD 17p duplications appear to be the most frequent cause of SHFLD. A ∼11.8 kb minimal critical region was identified encompassing a single gene, BHLHA9, a putative basic loop helix transcription factor. Whole mount in situ hybridisation showed expression restricted to the limb bud mesenchyme underlying the apical ectodermal ridge in mouse and zebrafish embryos. Knock down of bhlha9 in zebrafish resulted in shortening of the pectoral fins.

Conclusions

Genomic duplications encompassing BHLHA9 are associated with SHFLD and non-Mendelian inheritance characterised by a high degree of non-penetrance with sex bias. Knock-down of bhlha9 in zebrafish causes severe reduction defects of the pectoral fin, indicating a role for this gene in limb development.

Ectrodactyly

Penetrance

Limb development

Apical ectodermal ridge

Mendelian inheritance

10.1136/jmedgenet-2011-100409

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Citations (87)

A previously undescribed syndrome combining fibular agenesis/hypoplasia, oligodactylous clubfeet, anonychia/ungual hypoplasia, and other defects

American Journal of Medical Genetics Part A (2008)

Silvana Santos Eliete Pardono Maria Ione Ferreira da Costa Áurea Nogueira de Melo Zódja Graciani

Abstract We describe an apparently new genetic syndrome in six members of a family living in a remote area in Northeastern Brazil. This syndrome comprises: short stature due to a marked decrease in the length of the lower limbs (predominantly mesomelic with fibular agenesis/marked hypoplasia), grossly malformed/deformed clubfeet with severe oligodactyly, upper limbs with acromial dimples and variable motion limitation of the forearms and/or hands, severe nail hypoplasia/anonychia sometimes associated with mild brachydactyly and occasionally with pre‐axial polydactyly. This syndrome is apparently distinct from the syndrome of brachydactyly‐ectrodactyly with fibular aplasia or hypoplasia (OMIM 113310), the syndrome of fibular aplasia or hypoplasia, femoral bowing and poly‐, syn‐, and oligodactyly (OMIM 228930), and from other previously described conditions exhibiting fibular agenesis/hypoplasia. © 2008 Wiley‐Liss, Inc.

Brachydactyly

Aplasia

Agenesis

Ectrodactyly

Polydactyly

Syndactyly

Dysostosis

10.1002/ajmg.a.32580

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Citations (12)

Correspondence regarding Ballana et al., “Mitochondrial 12S rRNA gene mutations affect RNA secondary structure and lead to variable penetrance in hearing impairment”

Biochemical and Biophysical Research Communications (2006)

Ronaldo Serafim Abreu-Silva Ana Carla Batissoco Karina Lezirovitz Jihane Romanos Daniel Rincon

Penetrance

10.1016/j.bbrc.2006.03.049

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Citations (5)

Waardenburg Syndrome: The Contribution of Next-Generation Sequencing to the Identification of Novel Causative Variants

Audiology Research (2023)

William Bertani‐Torres Karina Lezirovitz D. Coutinho Eliete Pardono Silvia Souza da Costa

Waardenburg syndrome (WS) is characterized by hearing loss and pigmentary abnormalities of the eyes, hair, and skin. The condition is genetically heterogeneous, and is classified into four clinical types differentiated by the presence of dystopia canthorum in type 1 and its absence in type 2. Additionally, limb musculoskeletal abnormalities and Hirschsprung disease differentiate types 3 and 4, respectively. Genes PAX3, MITF, SOX10, KITLG, EDNRB, and EDN3 are already known to be associated with WS. In WS, a certain degree of molecularly undetected patients remains, especially in type 2. This study aims to pinpoint causative variants using different NGS approaches in a cohort of 26 Brazilian probands with possible/probable diagnosis of WS1 (8) or WS2 (18). DNA from the patients was first analyzed by exome sequencing. Seven of these families were submitted to trio analysis. For inconclusive cases, we applied a targeted NGS panel targeting WS/neurocristopathies genes. Causative variants were detected in 20 of the 26 probands analyzed, these being five in PAX3, eight in MITF, two in SOX10, four in EDNRB, and one in ACTG1 (type 2 Baraitser-Winter syndrome, BWS2). In conclusion, in our cohort of patients, the detection rate of the causative variant was 77%, confirming the superior detection power of NGS in genetically heterogeneous diseases.

SOX10

PAX3

Waardenburg syndrome

Proband

Microphthalmia-associated transcription factor

10.3390/audiolres14010002

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Citations (2)

Retention of progenitor cell phenotype in otospheres from guinea pig and mouse cochlea

Journal of Translational Medicine (2010)

Jeanne Oiticica Luiz Carlos M Barboza-Junior Ana Carla Batissoco Karina Lezirovitz Regina Célia Mingroni‐Netto

Culturing otospheres from dissociated organ of Corti is an appropriate starting point aiming at the development of cell therapy for hair cell loss. Although guinea pigs have been widely used as an excellent experimental model for studying the biology of the inner ear, the mouse cochlea has been more suitable for yielding otospheres in vitro. The aim of this study was to compare conditions and outcomes of otosphere suspension cultures from dissociated organ of Corti of either mouse or guinea pig at postnatal day three (P3), and to evaluate the guinea pig as a potential cochlea donor for preclinical cell therapy. Organs of Corti were surgically isolated from P3 guinea pig or mouse cochlea, dissociated and cultivated under non-adherent conditions. Cultures were maintained in serum-free DMEM:F12 medium, supplemented with epidermal growth factor (EGF) plus either basic fibroblast growth factor (bFGF) or transforming growth factor alpha (TGFα). Immunofluorescence assays were conducted for phenotype characterization. The TGFα group presented a number of spheres significantly higher than the bFGF group. Although mouse cultures yielded more cells per sphere than guinea pig cultures, sox2 and nestin distributed similarly in otosphere cells from both organisms. We present evidence that otospheres retain properties of inner ear progenitor cells such as self-renewal, proliferation, and differentiation into hair cells or supporting cells. Dissociated guinea pig cochlea produced otospheres in vitro, expressing sox2 and nestin similarly to mouse otospheres. Our data is supporting evidence for the presence of inner ear progenitor cells in the postnatal guinea pig. However, there is limited viability for these cells in neonatal guinea pig cochlea when compared to the differentiation potential observed for the mouse organ of Corti at the same developmental stage.

Nestin

Spiral ganglion

Cochlear duct

10.1186/1479-5876-8-119

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Citations (22)

Hearing aid effectiveness on patients with chronic tinnitus and associated hearing loss

Brazilian Journal of Otorhinolaryngology (2022)

Patricia Simonetti Laura Garcia E. Vasconcelos Mara Gândara Karina Lezirovitz Ítalo Roberto Torres de Medeiros

Our study aimed to measure the effectiveness of using HA in reducing the disturbance caused by tinnitus. 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). 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. Our study has provided evidence that HA fitting is a valuable treatment strategy for chronic tinnitus relief and associated hearing loss subtype of patient. 3.

Hearing aid

10.1016/j.bjorl.2022.03.002

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Citations (3)

Duplications of BHLHA9 are associated with ectrodactyly and tibia hemimelia inherited in non-Mendelian fashion

European Journal of Human Genetics (2012)

Silke B. Lohan SC Doelken Sigmar Stricker CW Ockeloen Renata Soares Thiele de Aguiar

Ectrodactyly

Mendelian inheritance

Source

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Citations (6)