ANTONIO MARCONDES LERARIO
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
12 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 12
- A novel homozygous 1-bp deletion in the NOBOX gene in two Brazilian sisters with primary ovarian failure(2017) FRANCA, Monica M.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; NISHI, Mirian Y.; PITA, Carmem C.; FONTENELE, Eveline G. P.; MENDONCA, Berenice B.Purpose Primary ovarian failure (POF) is characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women leading to infertility under the age of 40 years. POF is a heterogeneous disease with different causes, and several genes have been associated with the POF phenotype. Thus, Whole-exome sequencing (WES) was performed in a consanguineous family with two sisters affected by POF. Methods All exons of both sisters were massively sequenced by WES, and the segregation was confirmed by Sanger sequencing. Results The novel homozygous c.1489delT variant in the NOBOX gene was identified in the two sisters with POF. Their parents were heterozygous carriers of this variant and, therefore, consistent with an autosomal recessive mode of inheritance. The c.1489delT NOBOX variant has not been previously reported in any public available databases (1000Genomes, 6500ESP/EVS, ExAC, and gnomAD). Furthermore, this variant was neither present in 387 Brazilian exomes control individuals nor in 200 fertile Brazilian women screened by Sanger sequencing. Conclusion We report the first familial case of a novel homozygous NOBOX variant with an autosomal recessive mode of inheritance, thus allowing for a genetic diagnosis of primary ovarian failure.
- CD99 plays an important role in glioblastoma cell migration(2017) CARDOSO, Lais C.; LERARIO, Antonio M.; MARIE, Suely K.; SOARES, Roseli S.; OBA-SHINJO, Sueli M.
- Transcriptome analysis showed a Differential signature between invasive and non-invasive corticotrophinomas(2017) ARAUJO, Leonardo Jose Tadeu de; LERARIO, Antonio Marcondes; CASTRO, Margaret de; MARTINS, Clarissa Silva; BRONSTEIN, Marcello Delano; MACHADO, Marcio Carlos; TRARBACH, Ericka Barbosa; FRAGOSO, Maria Candida Barisson VillaresACTH-dependent hypercortisolism caused by a pituitary adenoma [Cushing's disease (CD)] is the most common cause of endogenous Cushing's syndrome. CD is often associated with several morbidities, including hypertension, diabetes, osteoporosis/bone fractures, secondary infections, and increased cardiovascular mortality. While the majority (approximate to 80%) of the corticotrophinomas visible on pituitary magnetic resonance imaging are microadenomas (MICs, <10 mm of diameter), some tumors are macroadenomas (MACs, >= 10 mm) with increased growth potential and invasiveness, exceptionally exhibiting malignant demeanor. In addition, larger and invasive MACs are associated with a significant increased risk of local complications, such as hypopituitarism and visual defects. Given the clinical and molecular heterogeneity of corticotrophinomas, the aim of this study was to investigate the pattern of genetic differential expression between MIC and MAC, including the invasiveness grade as a criterion for categorizing these tumors. In this study, were included tumor samples from patients with clinical, laboratorial, radiological, and histopathological diagnosis of hypercortisolism due to an ACTH-producing pituitary adenoma. Differential gene expression was studied using an Affymetrix microarray platform in 12 corticotrophinomas, classified as non-invasive MIC (n = 4) and MAC (n = 5), and invasive MAC (n = 3), according to modified Hardy criteria. Somatic mutations in USP8 were also investigated, but none of the patients exhibited USP8 variants. Differential expression analysis demonstrated that non-invasive MIC and MAC have a similar genetic signature, while invasive MACs exhibited a differential expression profile. Among the genes differentially expressed, we highlighted CCND2, ZNF676, DAPK1, and TIMP2, and their differential expression was validated through quantitative real-time PCR in another cohort of 15 non-invasive and 3 invasive cortocotrophinomas. We also identified potential biological pathways associated with growth and invasiveness, TGF-beta and G protein signaling pathways, DNA damage response pathway, and pathways associated with focal adhesion. Our study revealed a differential pattern of genetic signature in a subgroup of MAC, supporting a genetic influence on corticotrophinomas in patients with CD.
- Correlation between molecular features and genetic subtypes of Glioblastoma: critical analysis in 109 cases(2017) GALATRO, Thais F; SOLA, Paula; MORETTI, Isabele F; MIURA, Flavio K; OBA-SHINJO, Sueli M; MARIE, Suely KN; LERARIO, Antonio MOBJECTIVE: Glioblastoma, the most common and lethal brain tumor, is also one of the most defying forms of malignancies in terms of treatment. Integrated genomic analysis has searched deeper into the molecular architecture of GBM, revealing a new sub-classification and promising precision in the care for patients with specific alterations. METHOD: Here, we present the classification of a Brazilian glioblastoma cohort into its main molecular subtypes. Using a high-throughput DNA sequencing procedure, we have classified this cohort into proneural, classical and mesenchymal sub-types. Next, we tested the possible use of the overexpression of the EGFR and CHI3L1 genes, detected through immunohistochemistry, for the identification of the classical and mesenchymal subtypes, respectively. RESULTS: Our results demonstrate that genetic identification of the glioblastoma subtypes is not possible using single targeted mutations alone, particularly in the case of the Mesenchymal subtype. We also show that it is not possible to single out the mesenchymal cases through CHI3L1 expression. CONCLUSION: Our data indicate that the Mesenchymal subtype, the most malignant of the glioblastomas, needs further and more thorough research to be ensure adequate identification.
conferenceObject E74 LIKE ETS TRANSCRIPTION FACTOR 4 ( ELF4) IS A CANDIDATE GENE FOR X- LINKED FAMILIAL ISOLATED GROWTH HORMONE DEFICIENCY BY WHOLE EXOME SEQUENCING(2017) CORREA, Fernanda A.; FANG, Qing; LERARIO, Antonio M.; MA, Qianyi; OZEL, Bilge A.; LI, Jun Z.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; ARNHOLD, Ivo J. P.; CAMPER, Sally A.; MENDONCA, Berenice B.conferenceObject High Diagnostic Yield and Higher Proportion of Non-Collagen Defects in Adults with Osteogenesis Imperfecta Analyzed Using Targeted Massively Parallel Sequencing.(2017) FERNANDES, Adriana M.; ROCHA-BRAZ, Manuela G. M.; FRANCA, Monica M.; MARTIN, Regina M.; LERARIO, Antonio M.; MENDONCA, Berenice B.; FERRAZ-DE-SOUZA, Bruno- Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2(2017) VASQUES, Gabriela A.; HISADO-OLIVA, Alfonso; FUNARI, Mariana F. A.; LERARIO, Antonio M.; QUEDAS, Elisangela P. S.; SOLBERG, Paulo; HEATH, Karen E.; JORGE, Alexander A. L.Background: Heterozygous loss-of-function mutations in the natriuretic peptide receptor B gene (NPR2) are responsible for short stature in patients without a distinct phenotype. Some of these patients have been treated with recombinant human growth hormone (rhGH) therapy with a variable response. Case presentation: The proband was a healthy boy who presented at the age of 5.1 years with familial short stature (height SDS of -3.1). He had a prominent forehead, a depressed nasal bridge, centripetal fat distribution and a high-pitched voice resembling that of children with GH deficiency. His hormonal evaluation showed low insulin-like growth factor-1 (IGF-1) but a normal GH peak at a stimulation test. During the first year of rhGH treatment, his growth velocity increased from 3.4 to 10.4 cm/year (height SDS change of +1.1). At the last visit, he was 8.8 years old and still on treatment, his growth velocity was 6.4 cm/year and height SDS was -1.8. Results: We identified through exome sequencing a novel heterozygous loss-of-function NPR2 mutation (c.2905G>C; p.Val969Leu). Cells cotransfected with the p. Val969Leu mutant showed a significant decrease in cyclic guanosine monophosphate (cGMP) production compared to the wild type (WT), suggesting a dominant negative effect. Conclusions: This case reveals a novel heterozygous loss-of-function NPR2 mutation responsible for familial short stature and the good response of rhGH therapy in this patient.
- A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family(2017) FRANCA, Monica M.; LERARIO, Antonio M.; FUNARI, Mariana F. A.; NISHI, Mirian Y.; NARCIZO, Amanda M.; MELLO, Maricilda P. de; GUERRA-JUNIOR, Gil; MACIEL-GUERRA, Andrea T.; MENDONCA, Berenice B.Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46, XX girl and a 46, XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c. 1298C> A; p. Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/ EVS) and Brazilian exome controls.Moreover, it is highly conserved and predicted as deleteriousin all prediction sites analyzed. In conclusion, the novel homozygousFSHR variant observed in 2 siblings with HH canexpand the spectrum of FSHR mutations in humans. (C) 2017 S. Karger AG, Basel
- New evidences on the regulation of SF-1 expression by POD1/TCF21 in adrenocortical tumor cells(2017) FRANCA, Monica Malheiros; LERARIO, Antonio M.; FRAGOSO, Maria Candida B. V.; LOTFI, Claudimara Ferini PaciccoOBJECTIVES: Transcription Factor 21 represses steroidogenic factor 1, a nuclear receptor required for gonadal development, sex determination and the regulation of adrenogonadal steroidogenesis. The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors. METHODS: We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA. In addition, using overexpression of Transcription Factor 21 in human adrenocortical carcinoma cells, we analyzed the protein expression of steroidogenic factor 1 using Western blotting. RESULTS: Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells. Additionally, Transcription Factor 21 overexpression inhibited the protein expression of steroidogenic factor 1 by 0.41-fold and 0.64-fold in two different adult adrenocortical carcinoma cell cultures, H295R and T36, respectively. CONCLUSIONS: Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors.
- Transcriptome analysis of astrocytoma versus non-neoplastic human microglia(2017) GALATRO, Thais Fernanda; LERARIO, Antonio M.; OBA-SHINJO, Sueli M.; EGGEN, Bart J.; MARIE, Suely K.