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1.
Blood ; 132(5): 469-483, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-29891534

RESUMO

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.


Assuntos
Éxons , Predisposição Genética para Doença , Mutação , Policitemia/genética , Splicing de RNA , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Criança , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Policitemia/classificação , Policitemia/patologia , Adulto Jovem , Doença de von Hippel-Lindau/patologia
2.
Am J Med Genet A ; 173(2): 531-536, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27868338

RESUMO

Autosomal dominant genetic diseases can occur de novo and in the form of somatic mosaicism, which can give rise to a less severe phenotype, and make diagnosis more difficult given the sensitivity limits of the methods used. We report the case of female child with a history of surgery for syndactyly of the hands and feet, who was admitted at 6 years of age to a pediatric intensive care unit following cardiac arrest. The electrocardiogram (ECG) showed a long QT interval that on occasions reached 500 ms. Despite the absence of facial dysmorphism and the presence of normal psychomotor development, a diagnosis of Timothy syndrome was made given the association of syndactyly and the ECG features. Sanger sequencing of the CACNA1C gene, followed by sequencing of the genes KCNQ1, KCNH2, KCNE1, KCNE2, were negative. The subsequent analysis of a panel of genes responsible for hereditary cardiac rhythm disorders using Haloplex technology revealed a recurrent mosaic p.Gly406Arg missense mutation of the CACNA1C gene in 18% of the cells. This mosaicism can explain the negative Sanger analysis and the less complete phenotype in this patient. Given the other cases in the literature, mosaic mutations in Timothy syndrome appear more common than previously thought. This case demonstrates the importance of using next-generation sequencing to identify mosaic mutations when the clinical picture supports a specific mutation that is not identified using conventional testing. © 2016 Wiley Periodicals, Inc.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Canais de Cálcio Tipo L/genética , Estudos de Associação Genética , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Mosaicismo , Mutação , Fenótipo , Sindactilia/diagnóstico , Sindactilia/genética , Alelos , Substituição de Aminoácidos , Criança , Códon , Análise Mutacional de DNA , Eletrocardiografia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
3.
Artigo em Inglês | MEDLINE | ID: mdl-32466294

RESUMO

Despite considerable efforts in prevention and therapy, breast cancer remains a major public health concern worldwide. Numerous studies using breast cancer cell lines have shown the antiproliferative and pro-apoptotic effects of docosahexaenoic acid (DHA). Some studies have also demonstrated the inhibitory effect of DHA on the migration and invasion of breast cancer cells, making DHA a potential anti-metastatic agent. Thus, DHA has shown its potential as a chemotherapeutic adjuvant. However, the molecular mechanisms triggering DHA effects remain unclear, and the aim of this study was to provide a transcriptomic basis for further cellular and molecular investigations. Therefore, MDA-MB-231 cells were treated with 100 µM DHA for 1`2 h or 24 h before RNA-seq analysis. The results show the great impact of DHA-treatment on the transcriptome, especially after 24 h of treatment. The impact of DHA is particularly visible in genes involved in the cholesterol biosynthesis pathway that is strongly downregulated, and the endoplasmic reticulum (ER)-stress response that is, conversely, upregulated. This ER-stress and unfolded protein response could explain the pro-apoptotic effect of DHA. The expression of genes related to migration and invasion (especially SERPINE1, PLAT, and MMP11) is also impacted by DHA. In conclusion, this transcriptomic analysis supports the antiproliferative, pro-apoptotic and anti-invasive effects of DHA, and provides new avenues for understanding its molecular mechanisms.


Assuntos
Neoplasias da Mama/genética , Ácidos Docosa-Hexaenoicos/metabolismo , Apoptose , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Colesterol , Regulação para Baixo , Humanos , Transcriptoma , Regulação para Cima
4.
Cell Death Dis ; 11(1): 19, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31907355

RESUMO

Drug resistance limits the therapeutic efficacy in cancers and leads to tumor recurrence through ill-defined mechanisms. Glioblastoma (GBM) are the deadliest brain tumors in adults. GBM, at diagnosis or after treatment, are resistant to temozolomide (TMZ), the standard chemotherapy. To better understand the acquisition of this resistance, we performed a longitudinal study, using a combination of mathematical models, RNA sequencing, single cell analyses, functional and drug assays in a human glioma cell line (U251). After an initial response characterized by cell death induction, cells entered a transient state defined by slow growth, a distinct morphology and a shift of metabolism. Specific genes expression associated to this population revealed chromatin remodeling. Indeed, the histone deacetylase inhibitor trichostatin (TSA), specifically eliminated this population and thus prevented the appearance of fast growing TMZ-resistant cells. In conclusion, we have identified in glioblastoma a population with tolerant-like features, which could constitute a therapeutic target.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Temozolomida/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Modelos Biológicos , Análise de Célula Única , Temozolomida/farmacologia
5.
Oncotarget ; 9(22): 15883-15894, 2018 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-29662614

RESUMO

The PGC-1 (Peroxisome proliferator-activated receptor Gamma Coactivator-1) family of coactivators (PGC-1α, PGC-1ß, and PRC) plays a central role in the transcriptional control of mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) processes. These coactivators integrate mitochondrial energy production into cell metabolism using complementary pathways. The XTC.UC1 cell line is a mitochondria-rich model of thyroid tumors whose biogenesis is almost exclusively dependent on PRC. Here we aim to propose an integrative view of the cellular pathways regulated by PRC through integration of cDNA and miRNA microarray data and chromatin immunoprecipitation results obtained from XTC.UC1 cells invalidated for PRC. This study showes that PRC induces a complex network of cellular functions interacting with at least one to five of the studied transcription factors (Estrogen Related Receptor alpha, ERR1; Nuclear-Respiratory Factors, NRF1 and NRF2; cAMP Response Element Binding, CREB; and Ying Yang, YY1). Our data confirm that ERR1 is a key partner of PRC in the regulation of mitochondrial functions and suggest a potential role of this complex in RNA processing. PRC is also involved in transcriptional regulatory complexes targeting 12 miRNAs, five of which are involved in the control of the OXPHOS process. Our findings demonstrate that the PRC coactivator can act in complex with several transcription factors and regulate miRNA expression to control the fine regulation of main metabolic functions in the cell. Therefore, in PGC-1α/ß-associated pathologies, PRC, as a metabolic sensor, may ensure mitochondrial homeostasis.

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