LUCIANA RIBEIRO MONTENEGRO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals(2016) DOMENICE, Sorahia; MACHADO, Aline Zamboni; FERREIRA, Frederico Moraes; FERRAZ-DE-SOUZA, Bruno; LERARIO, Antonio Marcondes; LIN, Lin; NISHI, Mirian Yumie; GOMES, Nathalia Lisboa; SILVA, Thatiana Evelin da; SILVA, Rosana Barbosa; CORREA, Rafaela Vieira; MONTENEGRO, Luciana Ribeiro; NARCISO, Amanda; COSTA, Elaine Maria Frade; ACHERMANN, John C.; MENDONCA, Berenice BilharinhoSteroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Mullerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. (c) 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
- Effects of Type 1 Insulin-Like Growth Factor Receptor Silencing in a Human Adrenocortical Cell Line(2016) RIBEIRO, T. C.; JORGE, A. A.; MONTENEGRO, L. R.; ALMEIDA, M. Q.; FERRAZ-DE-SOUZA, B.; NISHI, M. Y.; MENDONCA, B. B.; LATRONICO, A. C.Type 1 insulin-like growth factor receptor (IGF-1R) is overexpressed in a variety of human cancers, including adrenocortical tumors. The aim of the work was to investigate the effects of IGF-1R downregulation in a human adrenocortical cell line by small interfering RNA (siRNA). The human adrenocortical tumor cell line NCI H295R was transfected with 2 specific IGF1R siRNAs (#1 and #2) and compared with untreated cells and a negative control siRNA. IGF1R expression was determined by quantitative reverse-transcription PCR (qRTPCR) and Western blot. The effects of IGF-1R downregulation on cell proliferation and apoptosis were assessed. IGF-1R levels were significantly decreased in cells treated with IGF1R siRNA #1 or #2. Relative expression of IGF1R mRNA decreased approximately 50 % and Western blot analysis revealed a 30 % of reduction in IGF-1R protein. Downregulation of this gene resulted in 40 % reduction in cell growth in vitro and 45 % increase in apoptosis using siRNA #2. These findings demonstrate that decreasing IGF1R mRNA and protein expression in NCI H295R cells can partially inhibit adrenal tumor cell growth in vitro. Targeting IGF-1R is a promising therapy for pediatric malignant adrenocortical tumor and can still be an option for adult adrenocortical cancer based on personalized genomic tumor profiling.
- A homozygous point mutation in the GH1 promoter (c.-223C > T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD)(2016) MADEIRA, Joao L. O.; JORGE, Alexander A. L.; MARTIN, Regina M.; MONTENEGRO, Luciana R.; FRANCA, Marcela M.; COSTALONGA, Everlayny F.; CORREA, Fernanda A.; OTTO, Aline P.; ARNHOLD, Ivo J. P.; FREITAS, Helayne S.; MACHADO, Ubiratan F.; MENDONCA, Berenice B.; CARVALHO, Luciani R.Context: Mutations in the GH1 promoter are a rare cause of isolated growth hormone deficiency (IGHD). Objective: To identify the molecular aetiology of a family with IGHD. Design: DNA sequencing, electromobility shift (EMSA) and luciferase reporter assays. Setting: University Hospital. Patients: Three siblings (2M) born to consanguineous parents presented with IGHD with normal pituitary on MRI. Methods: The GH1 proximal promoter, locus control region, five exons and four introns as well as GHRHR gene were sequenced in genomic DNA by Sanger method. DNA- protein interaction was evaluated by EMSA in nuclear extracts of GH3 pituitary cells. Dual-luciferase reporter assays were performed in cells transiently transfected with plasmids containing four different combinations of GH1 allelic variants (AV). Results: The patients harboured two homozygous variants (c.-185T>C and c.-223C>T) in the GH1 promoter within a highly conserved region and predicted binding sites for POU1F1/SP1 and SP1 respectively. The parents and brother were carriers and these variants were absent in 100 controls. EMSA demonstrated absent binding of GH3 nuclear extract to the c.-223C>T variant and normal binding of both POU1F1 protein and GH3 nuclear extract to the c.-185T>C variant. In contrast to GH1 promoter with AV only at c.-185, the GH1 promoter containing the AV only at c.-223 and at both positions drove significantly less expression of luciferase compared with the promoter containing either positions wild type in luciferase reporter assays. Conclusion: To our knowledge, c.-223C>T is the first homozygous point mutation in the GH1 promoter that leads to short stature due to IGHD.
- Clinical and Hormonal Features of a Male Adolescent with Congenital Isolated Follicle-Stimulating Hormone Deficiency(2016) SIMSEK, Enver; MONTENEGRO, Luciana R.; BINAY, Cigdem; DEMIRAL, Meliha; ACIKALIN, Mustafa Fuat; LATRONICO, Ana ClaudiaAim: Our aim was to describe the clinical and genetic findings in an adolescent male with isolated follicle-stimulating hormone (FSH) deficiency and demonstrate the efficacy of recombinant human FSH (rhFSH) replacement in this case. Methods: A 14.5-year-old adolescent male was referred with normal pubertal development and small testes. Serum testosterone, FSH, and luteinising hormone (LH) were measured at baseline and after gonadotropin-releasing hormone (GnRH) stimulation. Testicular biopsy was performed, and rhFSH replacement was administered for 6 months. The patient's FSH beta gene was amplified and sequenced. Results: Basal and GnRH-stimulated FSH levels were undetectable, in contrast with increased LH levels under both conditions. Histopathological investigation of a testicular biopsy specimen revealed a reduced number of Sertoli cells, the absence of germ cells, Leydig cell hyperplasia, and a thickened basement membrane in seminiferous tubules. The testicular size changed from 1 ml at baseline to 6 ml after 6 months of rhFSH replacement. Sequencing of the FSH beta gene exon 3 revealed a new missense mutation (c.364T>C, resulting in p.Cys122Arg) in a homozygous state in the patient; both parents and a sister carried the same mutation in a heterozygous state. We also compared our case with all similar cases published previously. Conclusion: We herein described an adolescent male with isolated FSH deficiency due to a novel FSH beta gene mutation associated with a prepubertal testes size and normal virilisation. (C) 2015 S. Karger AG, Basel
conferenceObject A New GNRH1 Mutation in a Boy with Congenital Isolated Hypogonadotropic Hypogonadism(2016) LIMA, L. Guimaraes; MONTENEGRO, L. Ribeiro; LERARIO, A. Marcondes; NISHI, M.; MENDONCA, B. B.; LATRONICO, A. C.; SILVEIRA, L. Ferreira Gontijo