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1.
Am J Med Genet A ; 164A(4): 1069-74, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24459084

RESUMO

Pure/direct duplications on the long arm of chromosome 4 represent an infrequent chromosomal finding. Description of clinical findings in 30 patients has resulted in defining the 4q-associated phenotype. However, such duplications have not been molecularly or genomically characterized yet, limiting genotype-phenotype correlation. We report on the first two patients with a duplication involving the distal third of 4q that are characterized molecularly and genomically. Clinical features in our patients typical of 4q duplication syndrome included mild intellectual disability, cranial malformation, minor facial dysmorphism, and digital anomaly. Duplication of the segment 4q33-4q34, appears to be the critical region resulting in the phenotype associated with 4q duplication syndrome. The genes GLRA3, GMP6A that are invovled in neurogenesis and HAND2 in craniofacial development, within the duplicated region of 4q, may play a key role in the clinical phenotype. As more reporting on molecular characterization of 4q duplication becomes available, the role of these underlying genes may become clearer.


Assuntos
Anormalidades Múltiplas/genética , Genes Duplicados , Trissomia/genética , Pré-Escolar , Cromossomos Humanos Par 4/genética , Hibridização Genômica Comparativa/métodos , Humanos , Masculino , Fenótipo
2.
Mol Endocrinol ; 22(3): 609-22, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18048642

RESUMO

Estrogen has direct and indirect effects on mitochondrial activity, but the mechanisms mediating these effects remain unclear. Others reported that long-term estradiol (E(2)) treatment increased nuclear respiratory factor-1 (NRF-1) protein in cerebral blood vessels of ovariectomized rats. NRF-1 is a transcription factor that regulates the expression of nuclear-encoded mitochondrial genes, e.g. mitochondrial transcription factor A (TFAM), that control transcription of the mitochondrial genome. Here we tested the hypothesis that E(2) increases NRF-1 transcription resulting in a coordinate increase in the expression of nuclear- and mitochondrial- encoded genes and mitochondrial respiratory activity. We show that E(2) increased NRF-1 mRNA and protein in MCF-7 breast and H1793 lung adenocarcinoma cells in a time-dependent manner. E(2)-induced NRF-1 expression was inhibited by the estrogen receptor (ER) antagonist ICI 182,780 and actinomycin D but not by phosphoinositide-3 kinase and MAPK inhibitors, indicating a genomic mechanism of E(2) regulation of NRF-1 transcription. An estrogen response element (ERE) in the NRF-1 promoter bound ER alpha and ER beta in vitro, and E(2) induced ER alpha and ER beta recruitment to this ERE in chromatin immunoprecipitation assays in MCF-7 cells. The NRF-1 ERE activated reporter gene expression in transfected cells. Small interfering RNA to ER alpha and ER beta revealed that ER alpha mediates E(2)-induced NRF-1 transcription. The E(2)-induced increase in NRF-1 was followed by increased TFAM and the transcription of Tfam-regulated mitochondrial DNA-encoded COI and NDI genes and increased mitochondrial biogenesis. Knockdown of NRF-1 blocked E(2) stimulation of mitochondrial biogenesis and activity, indicating a mechanism by which estrogens regulate mitochondrial function by increasing NRF-1 expression.


Assuntos
Estradiol/farmacologia , Mitocôndrias/efeitos dos fármacos , Fator 1 Nuclear Respiratório/biossíntese , Transcrição Gênica/fisiologia , Western Blotting , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Estradiol/análogos & derivados , Antagonistas de Estrogênios/farmacologia , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Fulvestranto , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Nitrilas/farmacologia , Fator 1 Nuclear Respiratório/genética , Fenóis , Regiões Promotoras Genéticas/efeitos dos fármacos , Propionatos/farmacologia , Pirazóis/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
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