ANTONIO MARCONDES LERARIO
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
17 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 17
conferenceObject Whole-Exome Sequencing Reveals RAD51B Variant in Two Sisters with Primary Ovarian Failure(2016) FRANCA, Monica; FUNARI, Mariana; NISHI, Mirian; DOMENICE, Sorahia; LATRONICO, Ana Claudia; JORGE, Alexander; LERARIO, Antonio; MENDONCA, Berenice- Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism(2021) RASSI-CRUZ, Marcela; MARIA, Andrea G.; FAUCZ, Fabio R.; LONDON, Edra; VILELA, Leticia A. P.; SANTANA, Lucas S.; BENEDETTI, Anna Flavia F.; GOLDBAUM, Tatiana S.; TANNO, Fabio Y.; SROUGI, Vitor; CHAMBO, Jose L.; PEREIRA, Maria Adelaide A.; CAVALCANTE, Aline C. B. S.; CARNEVALE, Francisco C.; PILAN, Bruna; BORTOLOTTO, Luiz A.; DRAGER, Luciano F.; LERARIO, Antonio M.; LATRONICO, Ana Claudia; V, Maria Candida B. Fragoso; MENDONCA, Berenice B.; ZERBINI, Maria Claudia N.; STRATAKIS, Constantine A.; ALMEIDA, Madson Q.Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, 'sporadic' bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of gene tic etiologies of PA.
article 9 Citação(ões) na Scopus Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor(2011) LIMA, Lorena de Oliveira; LERARIO, Antonio Marcondes; ALENCAR, Guilherme Asmar; BRITO, Luciana Pinto; ALMEIDA, Madson Queiroz; DOMENICE, Sorahia; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barrison VillaresThe occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient. Arq Bras Endocrinol Metab. 2011;55(1) 72-7- Targeted Assessment of G0S2 Methylation Identifies a Rapidly Recurrent, Routinely Fatal Molecular Subtype of Adrenocortical Carcinoma(2019) MOHAN, Dipika R.; LERARIO, Antonio Marcondes; ELSE, Tobias; MUKHERJEE, Bhramar; ALMEIDA, Madson Q.; VINCE, Michelle; REGE, Juilee; MARIANI, Beatriz M. P.; ZERBINI, Maria Claudia N.; MENDONCA, Berenice B.; LATRONICO, Ana Claudia; MARIE, Suely K. N.; RAINEY, William E.; GIORDANO, Thomas J.; V, Maria Candida B. Fragoso; HAMMER, Gary D.Purpose: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with few therapies; however, patients with locoregional disease have variable outcomes. The Cancer Genome Atlas project on ACC (ACC-TCGA) identified that cancers of patients with homogeneously rapidly recurrent or fatal disease bear a unique CpG island hypermethylation phenotype, ""CIMP-high."" We sought to identify a biomarker that faithfully captures this subgroup. Experimental Design: We analyzed ACC-TCGA data to characterize differentially regulated biological processes, and identify a biomarker that is methylated and silenced exclusively in CIMP-high ACC. In an independent cohort of 114 adrenocortical tumors (80 treatment-naive primary ACC, 22 adrenocortical adenomas, and 12 non-naive/nonprimary ACC), we evaluated biomarker methylation by a restriction digest/qPCR-based approach, validated by targeted bisulfite sequencing. We evaluated expression of this biomarker and additional prognostic markers by qPCR. Results: We show that CIMP-high ACC is characterized by upregulation of cell cycle andDNAdamage response programs, and identify that hypermethylation and silencing of G0S2 distinguishes this subgroup. We confirmed G0S2 hypermethylation and silencing is exclusive to 40% of ACC, and independently predicts shorter disease- free and overall survival (median 14 and 17 months, respectively). Finally, G0S2 methylation combined with validated molecular markers (BUB1B-PINK1) stratifies ACC into three groups, with uniformly favorable, intermediate, and uniformly dismal outcomes. Conclusions: G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal ACC, amenable to targeted assessment using routine molecular diagnostics. Assessing G0S2 methylation is straightforward, feasible for clinical decision-making, and will enable the direction of efficacious adjuvant therapies for patients with aggressive ACC.
conferenceObject Development of Virilizing Adrenocortical Carcinoma during Pregnancy: Case Report(2014) NAKAGUMA, Marilena; MINANNI, Carlos Andre; MIRANDA, Mirela Costa de; LERARIO, Antonio M.; MENDONCA, Berenice B.; LATRONICO, Ana Claudia; ALMEIDA, Madson Q.; FRAGOSO, Maria Candida B. V.- Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer(2015) FARIA, Andre M.; SBIERA, Silviu; RIBEIRO, Tamaya C.; SOARES, Ibere C.; MARIANI, Beatriz M. P.; FREIRE, Daniel S.; SOUSA, Gabriela R. V. de; LERARIO, Antonio M.; RONCHI, Cristina L.; DEUTSCHBEIN, Timo; WAKAMATSU, Alda; ALVES, Venancio A. F.; ZERBINI, Maria Claudia N.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.; LATRONICO, Ana Claudia; FASSNACHT, Martin; ALMEIDA, Madson Q.ObjectiveLIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs). Patients and methodsLIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. ResultsLIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (P=001), but for overall survival only a trend was detectable (P=0117). In the multivariate analysis, only Ki67 index 10% (HR 46, P=0000) and weak LIN28 protein expression (HR 20, P=003) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 1334 (from 24 to 5193); P=0011] and was highly associated with reduced overall (P=001) and disease-free survival (P=001). However, mir-9 prognostic role should be further evaluated in a larger cohort. ConclusionWeak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.
- POD-1 binding to the E-box sequence inhibits SF-1 and StAR expression in human adrenocortical tumor cells(2013) FRANCA, Monica Malheiros; FERRAZ-DE-SOUZA, Bruno; SANTOS, Mariza Gerdulo; LERARIO, Antonio Marcondes; FRAGOSO, Maria Candida Barisson Villares; LATRONICO, Ana Claudia; KUICK, Rork D.; HAMMER, Gary D.; LOTFI, Claudimara F. P.Pod-1/Tcf21 is expressed at epithelial-mesenchymal interaction sites during development of many organs. Different approaches have demonstrated that Pod-1 transcriptionally inhibits Sf-1/NR5A1 during gonadal development. Disruption of Sf-1 can lead to disorders of adrenal development, while increased dosage of SF-1 has been related to increased adrenal cell proliferation and tumorigenesis. In this study, we analyzed whether POD-1 overexpression inhibits the endogenous Sf-1 expression in human and mouse adrenocortical tumor cells. Cells were transiently transfected with luciferase reporter gene under the control of Sf-1 promoter and with an expression vector encoding Pod-1. Pod-1 construct inhibited the transcription of the Sf1/Luc reporter gene in a dose-dependent manner in mouse Y-1 adrenocortical carcinoma (ACC) cells, and inhibited endogenous SF-1 expression in the human H295R and ACC-T36 adrenocortical carcinoma cells. These results were validated by chromatin immunoprecipitation assay with POD-1-transfected H295R cells using primers specific to E-box sequence in SF-1 promoter region, indicating that POD-1 binds to the SF-1 E-box promoter. Moreover, POD-1 over-expression resulted in a decrease in expression of the SF-1 target gene, StAR (Steroidogenic Acute Regulatory Protein). Lastly, while the induced expression of POD-1 did not affect the cell viability of H295R/POD-1 or ACC-T36/POD-1 cells, the most significantly enriched KEGG pathways for genes negatively correlated to POD-1/TCF21 in 33 human ACCs were those associated with cell cycle genes.
- New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism(2019) AMATO, Lorena Guimaraes Lima; MONTENEGRO, Luciana Ribeiro; LERARIO, Antonio Marcondes; JORGE, Alexander Augusto Lima; GUERRA JUNIOR, Gil; SCHNOLL, Caroline; RENCK, Alessandra Covallero; TRARBACH, Ericka Barbosa; COSTA, Elaine Maria Frade; MENDONCA, Berenice Bilharinho; LATRONICO, Ana Claudia; SILVEIRA, Leticia Ferreira GontijoContext: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective: Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients: A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions: This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.
- Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort(2020) BARROSO, Priscila Sales; JORGE, Alexander Augusto Lima; LERARIO, Antonio Marcondes; MONTENEGRO, Luciana Ribeiro; VASQUES, Gabriela Andrade; AMATO, Lorena Guimaraes Lima; SILVEIRA, Leticia Ferreira Gontijo; MENDONCA, Berenice Bilharinho; LATRONICO, Ana ClaudiaIntroduction:Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50-75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood.Objective:To characterize the clinical and genetic features of a CDGP cohort.Methods:Fifty-nine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development.Results:All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 +/- 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP -cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10,GHSR,CHD7,SPRY4, WDR11, SEMA3A,andIL17RD).IGSF10andGHSRwere the most prevalent affected genes in this group.Conclusions:Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.
conferenceObject Mutation and Expression Analysis of DICER1 and Mir-103 in Pediatric and Adult Adrenocortical Tumors(2014) SOUSA, Gabriela R. V.; RIBEIRO, Tamaya C.; FARIA, Andre M.; MARIANI, Beatriz M. P.; LERARIO, Antonio M.; ZERBINI, Maria Claudia N.; SOARES, Ibere C.; WAKAMATSU, Alda; ALVES, Venancio A. F.; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.; LATRONICO, Ana Claudia; ALMEIDA, Madson Q.