LUCIANI RENATA SILVEIRA DE CARVALHO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
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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- PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without beta-catenin mutations(2011) CANI, Carolina M. G.; MATUSHITA, Hamilton; CARVALHO, Luciani R. S.; SOARES, Ibere C.; BRITO, Luciana P.; ALMEIDA, Madson Q.; MENDONCA, Berenice B.INTRODUCTION: Activating mutations in exon 3 of the beta-catenin gene are involved in the pathogenesis of adamantinomatous craniopharyngiomas. Recently, the interaction between beta-catenin and PROP1 has been shown to be responsible for pituitary cell lineage determination. We hypothesized that dysregulated PROP1 expression could also be involved in the pathogenesis of craniopharyngiomas. OBJECTIVES: To determine whether dysregulated gene expression was responsible for tumor pathogenesis in adamantinomatous craniopharyngiomas, the beta-catenin gene was screened for mutations, and the expression of the beta-catenin gene and PROP1 was evaluated. METHODS: The beta-catenin gene was amplified and sequenced from 14 samples of adamantinomatous craniopharyngiomas. PROP1 and beta-catenin gene expression was assessed by real-time RT-PCR from 12 samples, and beta-catenin immunohistochemistry was performed on 11 samples. RESULTS: Mutations in the beta-catenin gene were identified in 64% of the adamantinomatous craniopharyngiomas samples. Evidence of beta-catenin gene overexpression was found in 71% of the tumors with beta-catenin mutations and in 40% of the tumors without mutations, and beta-catenin immunohistochemistry revealed a nuclear staining pattern for each of the analyzed samples. PROP1 expression was undetectable in all of the tumor samples. CONCLUSION: We found evidence of beta-catenin gene overexpression in the majority of adamantinomatous craniopharyngiomas, and we also detected a nuclear beta-catenin staining pattern regardless of the presence of a beta-catenin gene mutation. These results suggest that WNT signaling activation plays an important role in the pathogenesis of adamantinomatous craniopharyngiomas. Additionally, this study was the first to evaluate PROP1 expression in adamantinomatous craniopharyngiomas, and the absence of PROP1 expression indicates that this gene is not involved in the pathogenesis of this tumor, at least in this cohort.
- Absence of GH-Releasing Hormone (GHRH) Mutations in Selected Patients with Isolated GH Deficiency(2011) FRANCA, Marcela M.; JORGE, Alexander A. L.; ALATZOGLOU, Kyriaki S.; CARVALHO, Luciani R. S.; MENDONCA, Berenice B.; AUDI, Laura; CARRASCOSA, Antonio; DATTANI, Mehul T.; ARNHOLD, Ivo J. P.Context: Although numerous reports of mutations in GH1 and GHRHR (GHRH receptor) causing isolated GH deficiency (IGHD) have been published, mutations in GHRH itself have not been hitherto reported but are obvious candidates for GH deficiency. Objective: The aim of this study was to identify mutations in GHRH in a large cohort of patients with IGHD. Patients and Methods: DNA was isolated from 151 patients diagnosed with IGHD at national and international centers. Seventy-two patients fulfilled all the following criteria: severe short stature (height SD score <= -2.5), low peakGHafter stimulation (peak <= 5 ng/ml), eutopic posterior pituitary lobe, and absence of mutations in GH1 and GHRHR and therefore were strong candidates for GHRH mutations. The coding sequence and splice sites of GHRH were amplified by PCR with intronic primers and sequenced. Results: In five of 151 patients (four of 42 from Brazil), the GHRH c. 223 C>T, p. L75F change was identified in heterozygosity. This variant has been previously reported as a polymorphism and is more frequent in African than European and Asian populations. Six allelic variants (five novel) that do not predict change of amino acids or splice sites were identified in five patients: c. 147 C>T, p.S49S, IVS1 -70 G>A, IVS1 -74 T>C, IVS3 -47 del1, and IVS3 +7 G>A/IVS3 + 41 G>A. No functional mutations were found in this cohort. Conclusions: GHRH mutations were not identified in a selected cohort of patients with IGHD, suggesting that, if they exist, they may be an extremely rare cause of IGHD. Other, as-yet-unidentified genetic factors may be implicated in the genetic etiology of IGHD in our cohort. (J Clin Endocrinol Metab 96: E1457-E1460, 2011)