ANTONIO MARCONDES LERARIO
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
10 resultados
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Agora exibindo 1 - 10 de 10
- 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.
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- DAX1 Overexpression in Pediatric Adrenocortical Tumors: A Synergic Role with SF1 in Tumorigenesis(2015) SOUSA, G. R. V. de; SOARES, I. C.; FARIA, A. M.; DOMINGUES, V. B.; WAKAMATSU, A.; LERARIO, A. M.; ALVES, V. A. F.; ZERBINI, M. C. N.; MENDONCA, B. B.; FRAGOSO, M. C. B. V.; LATRONICO, A. C.; ALMEIDA, M. Q.DAX1 transcription factor is a key determinant of adrenogonadal development, acting as a repressor of SF1 targets in steroidogenesis. It was recently demonstrated that DAX1 regulates pluripotency and differentiation in murine embryonic stem cells. In this study, we investigated DAX1 expression in adrenocortical tumors (ACTs) and correlated it with SF1 expression and clinical parameters. DAX1 and SF1 protein expression were assessed in 104 ACTs from 34 children (25 clinically benign and 9 malignant) and 70 adults (40 adenomas and 30 carcinomas). DAX1 gene expression was studied in 49 ACTs by quantitative real-time PCR. A strong DAX1 protein expression was demonstrated in 74% (25 out of 34) and 24% (17 out of 70) of pediatric and adult ACTs, respectively ((2)=10.1, p=0.002). In the pediatric group, ACTs with a strong DAX1 expression were diagnosed at earlier ages than ACTs with weak expression [median 1.2 (range, 0.5-4.5) vs. 2.2 (0.9-9.4), p=0.038]. DAX1 expression was not associated with functional status in ACTs. Interestingly, a positive correlation was observed between DAX1 and SF1 protein expression in both pediatric and adult ACTs (r=0.55 for each group separately; p<0.0001). In addition, DAX1 gene expression was significantly correlated with SF1 gene expression (p<0.0001, r=0.54). In conclusion, DAX1 strong protein expression was more frequent in pediatric than in adult ACTs. Additionally, DAX1 and SF1 expression positively correlated in ACTs, suggesting that these transcription factors might cooperate in adrenocortical tumorigenesis.
- Genetic Evidence of the Association of DEAH-Box Helicase 37 Defects With 46,XY Gonadal Dysgenesis Spectrum(2019) SILVA, Thatiana Evilen da; GOMES, Nathalia Lisboa; LERARIO, Antonio Marcondes; KEEGAN, Catherine Elizabeth; NISHI, Mirian Yumi; CARVALHO, Filomena Marino; VILAIN, Eric; BARSEGHYAN, Hayk; MARTINEZ-AGUAYO, Alejandro; FORCLAZ, Maria Veronica; PAPAZIAN, Regina; PAULA, Leila Cristina Pedroso de; COSTA, Eduardo Correa; CARVALHO, Luciani Renata; JORGE, Alexander Augusto Lima; ELIAS, Felipe Martins; MITCHELL, Rod; COSTA, Elaine Maria Frade; MENDONCA, Berenice Bilharinho; DOMENICE, SorahiaContext: 46,XY Gonadal dysgenesis (GD) is a heterogeneous group of disorders with a wide phenotypic spectrum, including embryonic testicular regression syndrome (ETRS). Objective: To report a gene for 46,XY GD etiology, especially for ETRS. Design: Screening of familial cases of 46,XY GD using whole-exome sequencing and sporadic cases by target gene-panel sequencing. Setting: Tertiary Referral Center for differences/disorders of sex development (DSD). Patients and Interventions: We selected 87 patients with 46,XY DSD (17 familial cases from 8 unrelated families and 70 sporadic cases); 55 patients had GD (among them, 10 patients from 5 families and 8 sporadic cases had ETRS), and 32 patients had 46,XY DSD of unknown etiology. Results: We identified four heterozygous missense rare variants, classified as pathogenic or likely pathogenic in the Asp-Glu-Ala-His-box (DHX) helicase 37 (DHX37) gene in five families (n = 11 patients) and in six sporadic cases. Two variants were recurrent: p.Arg308Gln (in two families and in three sporadic cases) and p.Arg674Trp (in two families and in two sporadic cases). The variants were specifically associated with ETRS (7/14 index cases; 50%). The frequency of rare, predicted-to-be-deleterious DHX37 variants in this cohort (14%) is significantly higher than that observed in the Genome Aggregation Database (0.4%; P < 0.001). Immunohistochemistry analysis in human testis showed that DHX37 is mainly expressed in germ cells at different stages of testis maturation, in Leydig cells, and rarely in Sertoli cells. Conclusion: This strong genetic evidence identifies DHX37 as a player in the complex cascade of male gonadal differentiation and maintenance.
- BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells(2018) LESSEL, Davor; GEHBAUER, Christina; BRAMSWIG, Nuria C.; SCHLUTH-BOLARD, Caroline; VENKATARAMANAPPA, Sathish; GASSEN, Koen L. I. van; HEMPEL, Maja; HAACK, Tobias B.; BARESIC, Anja; GENETTI, Casie A.; FUNARI, Mariana F. A.; LESSEL, Ivana; KUHLMANN, Leonie; SIMON, Ruth; LIU, Pentao; DENECKE, Jonas; KUECHLER, Alma; KRUIJFF, Ineke de; SHOUKIER, Moneef; LEK, Monkol; MULLEN, Thomas; LUEDECKE, Hermann-Josef; LERARIO, Antonio M.; KOBBE, Robin; KRIEGER, Thorsten; DEMEER, Benedicte; LEBRUN, Marine; KEREN, Boris; NAVA, Caroline; BURATTI, Julien; AFENJAR, Alexandra; SHINAWI, Marwan; SACOTO, Maria J. Guillen; GAUTHIER, Julie; HAMDAN, Fadi F.; LABERGE, Anne-Marie; CAMPEAU, Philippe M.; LOUIE, Raymond J.; CATHEY, Sara S.; PRINZ, Immo; JORGE, Alexander A. L.; TERHAL, Paulien A.; LENHARD, Boris; WIECZOREK, Dagmar; STROM, Tim M.; AGRAWAL, Pankaj B.; BRITSCH, Stefan; TOLOSA, Eva; KUBISCH, ChristianThe transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.
article 36 Citação(ões) na Scopus Metabolic reprogramming: a new relevant pathway in adult adrenocortical tumors(2015) PINHEIRO, Celine; GRANJA, Sara; LONGATTO-FILHO, Adhemar; FARIA, Andre M.; FRAGOSO, Maria C. B. V.; LOVISOLO, Silvana M.; LERARIO, Antonio M.; ALMEIDA, Madson Q.; BALTAZAR, Fatima; ZERBINI, Maria C. N.Adrenocortical carcinomas (ACCs) are complex neoplasias that may present unexpected clinical behavior, being imperative to identify new biological markers that can predict patient prognosis and provide new therapeutic options. The main aim of the present study was to evaluate the prognostic value of metabolism-related key proteins in adrenocortical carcinoma. The immunohistochemical expression of MCT1, MCT2, MCT4, CD147, CD44, GLUT1 and CAIX was evaluated in a series of 154 adult patients with adrenocortical neoplasia and associated with patients' clinicopathological parameters. A significant increase in was found for membranous expression of MCT4, GLUT1 and CAIX in carcinomas, when compared to adenomas. Importantly MCT1, GLUT1 and CAIX expressions were significantly associated with poor prognostic variables, including high nuclear grade, high mitotic index, advanced tumor staging, presence of metastasis, as well as shorter overall and disease free survival. In opposition, MCT2 membranous expression was associated with favorable prognostic parameters. Importantly, cytoplasmic expression of CD147 was identified as an independent predictor of longer overall survival and cytoplasmic expression of CAIX as an independent predictor of longer disease-free survival. We provide evidence for a metabolic reprogramming in adrenocortical malignant tumors towards the hyperglycolytic and acid-resistant phenotype, which was associated with poor prognosis.- The role of fibroblast growth factor receptor 4 overexpression and gene amplification as prognostic markers in pediatric and adult adrenocortical tumors(2012) BRITO, Luciana Pinto; RIBEIRO, Tamaya Castro; ALMEIDA, Madson Q.; JORGE, Alexander Augusto de Lima; SOARES, Ibere Cauduro; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson Villares; LERARIO, Antonio Marcondes
- ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia(2014) ALENCAR, Guilherme Asmar; LERARIO, Antonio Marcondes; NISHI, Mirian Yumie; MARIANI, Beatriz Marinho de Paula; ALMEIDA, Madson Queiroz; TREMBLAY, Johanne; HAMET, Pavel; BOURDEAU, Isabelle; ZERBINI, Maria Claudia Nogueira; PEREIRA, Maria Adelaide Albergaria; GOMES, Gilberto Carlos; ROCHA, Manoel de Souza; CHAMBO, Jose Luis; LACROIX, Andre; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresContext: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. Objective: The aim of the present study was to identify the gene responsible for familial PMAH. Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.
- Evaluation of Downstream Regulatory Element Antagonistic Modulator Gene in Human Multinodular Goiter(2015) SHINZATO, Amanda; LERARIO, Antonio M.; LIN, Chin J.; DANILOVIC, Debora S.; MARUI, Suemi; TRARBACH, Ericka B.Background: DREAM (Downstream Regulatory Element Antagonistic Modulator) is a neuronal calcium sensor that was suggested to modulate TSH receptor activity and whose overexpression provokes an enlargement of the thyroid gland in transgenic mice. The aim of this study was to investigate somatic mutations and DREAM gene expression in human multinodular goiter (MNG). Material/Methods: DNA and RNA samples were obtained from hyperplastic thyroid glands of 60 patients (54 females) with benign MNG. DREAM mutations were evaluated by PCR and direct automatic sequencing, whereas relative quantification of mRNA was performed by real-time PCR. Over-and under-expression were defined as a 2-fold increase and decrease in comparison to normal thyroid tissue, respectively. RQ M (relative quantification mean); SD (standard deviation). Results: DREAM expression was detected in all nodules evaluated. DREAM mRNA was overexpressed in 31.7% of MNG (RQ M=6.26; SD=5.08), whereas 53.3% and 15% had either normal (RQ M=1.16; SD=0.46) or underexpression (RQ M=0.30; SD=0.10), respectively. Regarding DREAM mutations analysis, only previously described intronic polymorphisms were observed. Conclusions: We report DREAM gene expression in the hyperplastic thyroid gland of MNG patients. However, DREAM expression did not vary significantly, and was somewhat underexpressed in most patients, suggesting that DREAM upregulation does not significantly affect nodular development in human goiter.
- Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma(2016) ZHENG, Siyuan; CHERNIACK, Andrew D.; DEWAL, Ninad; MOFFITT, Richard A.; DANILOVA, Ludmila; MURRAY, Bradley A.; LERARIO, Antonio M.; ELSE, Tobias; KNIJNENBURG, Theo A.; CIRIELLO, Giovanni; KIM, Seungchan; ASSIE, Guillaume; MOROZOVA, Olena; AKBANI, Rehan; SHIH, Juliann; HOADLEY, Katherine A.; CHOUEIRI, Toni K.; WALDMANN, Jens; METE, Ozgur; ROBERTSON, A. Gordon; WU, Hsin-Ta; RAPHAEL, Benjamin J.; SHAO, Lina; MEYERSON, Matthew; DEMEURE, Michael J.; BEUSCHLEIN, Felix; GILL, Anthony J.; SIDHU, Stan B.; ALMEIDA, Madson Q.; FRAGOSO, Maria C. B. V.; COPE, Leslie M.; KEBEBEW, Electron; HABRA, Mouhammed A.; WHITSETT, Timothy G.; BUSSEY, Kimberly J.; RAINEY, William E.; ASA, Sylvia L.; BERTHERAT, Jerome; FASSNACHT, Martin; WHEELER, David A.; HAMMER, Gary D.; GIORDANO, Thomas J.; VERHAAK, Roel G. W.We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.