BERENICE BILHARINHO DE MENDONCA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
19 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 19
- PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation(2013) ARAUJO, Ricardo V.; CHANG, Claudia V.; CESCATO, Valter A. S.; FRAGOSO, Maria Candida B. V.; BRONSTEIN, Marcello D.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; CARVALHO, Luciani R. S.OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation.
bookPart Biologia molecular dos tumores endócrinos(2013) LERARIO, Antonio Marcondes; FRAGOSO, Maria Candida Barisson; BRITO, Luciana Pinto; MARTIN, Regina Matsunaga; TRARBACH, Erika Barbosa; MARUI, Suemi; TOLEDO, Rodrigo de Almeida; DOMENICE, Sorahia; MENDONçA, Berenice Bilharinho de- The benign spectrum of hypothalamic hamartomas: Infrequent epilepsy and normal cognition in patients presenting with central precocious puberty(2013) CUKIER, Priscilla; CASTRO, Luiz Henrique Martins; BANASKIWITZ, Natalie; TELES, Leandro Roberto; FERREIRA, Luiz Roberto Kobuti; ADDA, Carla Cristina; LEITE, Claudia da Costa; ARNHOLD, Ivo J. P.; MENDONCA, Berenice Bilharinho; LATRONICO, Ana Claudia; BRITO, Vinicius NahimePurpose: Hypothalamic hamartoma (HH) is the main structural cause of central precocious puberty (CPP). HH is frequently associated with cognitive impairment and epileptic encephalopathies. Disease severity in case series from neurology services may be biased towards more neurologically impaired patients. Aim: To perform a prospective cognitive evaluation in patients with HH presenting with CPP in an endocrinology outpatient clinic setting. Methods: We evaluated fifteen consecutive patients with CPP due to HH presenting to an endocrinology outpatient clinic. CPP was diagnosed at a median age of 0.7 yr (0.4-7 yr). Mean age at neurologic evaluation was 13.9 yrs. Eight patients (53.3%) were male. Epileptic seizures occurred in 5/15 (33%) patients. Two patients presented a single unprovoked seizure (SUS). Three patients were diagnosed with epilepsy. Cognitive evaluation, using age-appropriate Wechsler Intelligence Scale, was performed in 11 patients. Results: All patients without epilepsy, including two patients with a history of a SUS, had normal neurologic and cognitive evaluation. Epilepsy and SUS were only seen in patients with sessile HH. Three patients with epilepsy presented cognitive or behavioral findings. Reduced intelligence quotients (IQ), in the borderline range, were noted in both patients with epilepsy who underwent full cognitive evaluation. We found no significant correlation between HH diameter or shape and mean full-scale IQ. Conclusions: Patients who presented with isolated CPP without epilepsy displayed normal cognition when evaluated after a mean period of 13 years. Occurrence of epilepsy, seen in a minority of patients, but not of a single seizure, was associated with mild cognitive deficit and behavioral disturbances in this case series.
- TRANSSEXUAL GENITAL SURGERY: COMPLICATIONS AND FUNCTIONAL RESULTS AFTER 13 YEARS OF EXPERIENCE(2013) SIRCILI, Maria Helena; DENES, Francisco Tibor; TAVARES, Alessandro; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; CUNHA, Flavia Siqueira; SROUGI, Miguel; MENDONCA, Berenice
- Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: in vitro characterization of a novel mutation (p.Arg511Trp)(2013) LEAL, Andrea C.; MONTENEGRO, Luciana R.; SAITO, Renata F.; RIBEIRO, Tamaya C.; COUTINHO, Debora C.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Background Insulin-like growth factor 1 insensitivity caused by IGF1R mutations has been previously identified as one of the causes of growth impairment in children born small for gestational age (SGA). Objective To analyse the IGF1R in children born SGA. Subjects From an initial cohort of 54 sequential children born SGA, without catch-up growth, 25 children were selected for this IGF1R study due to the presence of serum IGF-1 values above the mean for their age and sex. Methods The proximal IGF1R promoter region, the entire coding region and the exonintron boundaries were directly sequenced, and multiplex ligation-dependent probe amplification analysis was performed. Fibroblast cultures were developed from one patient with a mutation for the in vitro characterization of IGF-1 insensitivity. Results The copy number variation analysis did not identify deletions involving the IGF1R gene. We identified two children carrying heterozygous nucleotide substitutions in IGF1R: c.16G>A/p.Gly6Arg and c.1531C>T/p.Arg511Trp. The first variant (p.Gly6Arg) was identified in control subjects (0 center dot 3%) and in a relative with normal growth; thus, it was considered to be a rare benign allelic variation. The second variant (p.Arg511Trp) was not found in 306 alleles from control subjects, and it segregated with the growth impairment phenotype in the patient's family. Fibroblasts obtained from this patient had a significantly reduced proliferative response and AKT phosphorylation after IGF-1 stimulation compared with control fibroblasts. Conclusion The identification of an inactivating IGF1R mutation in the present cohort should encourage further studies of larger series to establish the precise frequency of this molecular defect in children with growth impairment of a prenatal onset.
- Diabetes subdiagnosticado e necrose miocárdica: preditores de hiperglicemia no infarto do miocárdio(2013) LADEIRA, Renata Teixeira; BARACIOLI, Luciano Moreira; FAULIN, Tanize Espirito Santo; ABDALLA, Dulcineia Saes Parra; SEYDELL, Talita Mattos; MARANHAO, Raul Cavalcante; MENDONCA, Berenice Bilharinho; STRUNZ, Celia Cassaro; CASTRO, Isac de; NICOLAU, Jose CarlosBackground: Hyperglycemia in the acute phase of myocardial infarction is an important prognostic factor. However, its pathophysiology is not fully understood. Objective: To analyze simultaneously the correlation between hyperglycemia and biochemical markers related to stress, glucose and lipid metabolism, coagulation, inflammation, and myocardial necrosis. Methods: Eighty patients with acute myocardial infarction were prospectively included. The following parameters were analyzed: blood glucose; stress hormones (cortisol and norepinephrine); glucose metabolism factors [glycated hemoglobin (HbA1c); insulin]; lipoproteins (total cholesterol, LDL, HDL, minimally modified electronegative LDL, and adiponectin); glycerides (triglycerides, VLDL and fatty acids); coagulation factors (factor VII, fibrinogen, plasminogen activator inhibitor-1); inflammation (high-sensitivity C reactive protein); and myocardial necrosis (CK-MB and troponin). Continuous variables were converted into degrees of relevance using fuzzy logic. Results: Significant correlation was observed between hyperglycemia and glucose metabolism (p < 0.001), lipoproteins (p = 0.03), and necrosis factors (p = 0.03). In the multivariate analysis, only glucose metabolism (OR = 4.3; CI = 2.1-68.9; and p < 0.001) and myocardial necrosis (OR = 22.5; CI = 2-253; and p = 0.012) showed independent and significant correlation. For the analysis of the influence of history of diabetes mellitus, a regression model including only patients without diabetes mellitus was developed, and the results did not change. Finally, in the model adjusted for age, gender, and clinical variables (history of diabetes mellitus, hypertension and dyslipidemia), three variables maintained a significant and independent association with hyperglycemia: glucose metabolism (OR = 24.1; CI = 4.8-122.1; and p < 0.001), myocardial necrosis (OR = 21.9; CI = 1.3-360.9; and p = 0.03), and history of DM (OR = 27; CI = 3.7-195.7; and p = 0.001). Conclusion: Glucose metabolism and myocardial necrosis markers were the best predictors of hyperglycemia in patients with acute myocardial infarction.
- Molecular and Gene Network Analysis of Thyroid Transcription Factor 1 (TTF1) and Enhanced at Puberty (EAP1) Genes in Patients with GnRH-Dependent Pubertal Disorders(2013) CUKIER, Priscilla; WRIGHT, Hollis; RULFS, Tomke; SILVEIRA, Leticia Ferreira Gontijo; TELES, Milena Gurgel; MENDONCA, Berenice Bilharinho; ARNHOLD, Ivo J. P.; HEGER, Sabine; LATRONICO, Ana Claudia; OJEDA, Sergio R.; BRITO, Vinicius NahimeBackground/Aim: TTF1 and EAP1 are transcription factors that modulate gonadotropin-releasing hormone expression. We investigated the contribution of TTF1 and EAP1 genes to central pubertal disorders. Patients and Methods: 133 patients with central pubertal disorders were studied: 86 with central precocious puberty and 47 with normosmic isolated hypogonadotropic hypogonadism. The coding region of TTF1 and EAP1 were sequenced. Variations of polyglutamine and polyalanine repeats in EAP1 were analyzed by GeneScan software. Association of TTF1 and EAP1 to genes implicated in timing of puberty was investigated by meta-network framework GeneMANIA and Cytoscape software. Results: Direct sequencing of the TTF1 did not reveal any mutation or polymorphisms. Four EAP1 synonymous variants were identified with similar frequencies among groups. The most common EAP1 5'-distal polyalanine genotype was the homozygous 12/12, but the genotype 12/9 was identified in 2 central precocious puberty sisters without functional alteration in EAP1 transcriptional activity. TTF1 and EAP1 were connected, via genetic networks, to genes implicated in the control of menarche. Conclusion: No TTF1 or EAP1 germline mutations were associated with central pubertal disorders. TTF1 and EAP1 may affect puberty by changing expression in response to other members of puberty-associated gene networks, or by differentially affecting the expression of gene components of these networks. (C) 2013 S. Karger AG, Basel
- Y chromosome aberration in a patient with cloacal-bladder exstrophy-epispadias complex: an unusual finding(2013) NISHI, Mirian Yumie; MARTINS, Thais Cotrim; COSTA, Elaine Maria Frade; MENDONCA, Berenice Bilharinho; GIRON, Amilcar Martins; DOMENICE, SorahiaChromosome aberrations or genetic syndromes associated with cloacal-bladder exstrophy complex have rarely been reported. The aim of this report is to describe a 14 year-old female Brazilian patient with a complex urogenital malformation, short stature, lack of secondary sexual characteristics and Y chromosome aberration. A girl with cloacal bladder exstrophy complex was referred for evaluation of short stature and absence of secondary sexual characteristics. Pre-pubertal levels of gonadotropins and sex steroids were observed at the beginning of monitoring, but follow-up showed a progressive increase in testosterone levels. The patient underwent gonadectomy and testicular tissue was identified without dysgenetic characteristics. She had a 46,X,inv(Y)(p11.1q11.2) karyotype, normal SRY sequence, and no Y deletions. The pericentric inversion of Y chromosome apparently did not contribute to the development of the complex urogenital malformation in this patient. Currently, no teratogenic agent, environmental factor, or defective genes have been recognized as etiologic factors for this type of urogenital malformation. Arq Bras Endocrinol Metab. 2013; 57(2): 148-52
bookPart Manuseio do retardo puberal(2013) GADELHA, Patricia Sampaio; COSTA, Elaine Maria Frade; LATRONICO, Ana Claudia; MENDONçA, Berenice Bilharinho de- Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3(2013) ABREU, Ana Paula; DAUBER, Andrew; MACEDO, Delanie B.; NOEL, Sekoni D.; BRITO, Vinicius N.; GILL, John C.; CUKIER, Priscilla; THOMPSON, Iain R.; NAVARRO, Victor M.; GAGLIARDI, Priscila C.; RODRIGUES, Tania; KOCHI, Cristiane; LONGUI, Carlos Alberto; BECKERS, Dominique; ZEGHER, Francis de; MONTENEGRO, Luciana R.; MENDONCA, Berenice B.; CARROLL, Rona S.; HIRSCHHORN, Joel N.; LATRONICO, Ana Claudia; KAISER, Ursula B.BACKGROUND The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS Deficiency of MKRN3 causes central precocious puberty in humans.