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1.
Nat Genet ; 44(8): 928-33, 2012 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-22729222

RESUMO

The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target.


Assuntos
Tecido Adiposo/enzimologia , Tecido Adiposo/patologia , Tecido Conjuntivo/enzimologia , Tecido Conjuntivo/patologia , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Adolescente , Adulto , Sequência de Bases , Osso e Ossos/enzimologia , Osso e Ossos/patologia , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Ativação Enzimática/genética , Feminino , Humanos , Hiperplasia , Lactente , Masculino , Pessoa de Meia-Idade , Mosaicismo , Fenótipo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Síndrome
2.
Nature ; 434(7031): 325-37, 2005 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-15772651

RESUMO

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.


Assuntos
Cromossomos Humanos X/genética , Evolução Molecular , Genômica , Análise de Sequência de DNA , Animais , Antígenos de Neoplasias/genética , Centrômero/genética , Cromossomos Humanos Y/genética , Mapeamento de Sequências Contíguas , Troca Genética/genética , Mecanismo Genético de Compensação de Dose , Feminino , Ligação Genética/genética , Genética Médica , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , RNA/genética , Sequências Repetitivas de Ácido Nucleico/genética , Homologia de Sequência do Ácido Nucleico , Testículo/metabolismo
3.
Genes Chromosomes Cancer ; 36(4): 361-74, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12619160

RESUMO

We have designed DOP-PCR primers specifically for the amplification of large insert clones for use in the construction of DNA microarrays. A bioinformatic approach was used to construct primers that were efficient in the general amplification of human DNA but were poor at amplifying E. coli DNA, a common contaminant of DNA preparations from large insert clones. We chose the three most selective primers for use in printing DNA microarrays. DNA combined from the amplification of large insert clones by use of these three primers and spotted onto glass slides showed more than a sixfold increase in the human to E. coli hybridization ratio when compared to the standard DOP-PCR primer, 6MW. The microarrays reproducibly delineated previously characterized gains and deletions in a cancer cell line and identified a small gain not detected by use of conventional CGH. We also describe a method for the bulk testing of the hybridization characteristics of chromosome-specific clones spotted on microarrays by use of DNA amplified from flow-sorted chromosomes. Finally, we describe a set of clones selected from the publicly available Golden Path of the human genome at 1-Mb intervals and a view in the Ensembl genome browser from which data required for the use of these clones in array CGH and other experiments can be downloaded across the Internet.


Assuntos
Cromossomos Artificiais Bacterianos/genética , Cromossomos Artificiais de Bacteriófago P1/genética , Primers do DNA/genética , DNA/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase/métodos , Animais , Carcinoma de Células Renais/genética , Linhagem Celular , Aberrações Cromossômicas , DNA Bacteriano/genética , Drosophila melanogaster/genética , Escherichia coli/genética , Feminino , Humanos , Neoplasias Renais/genética , Linfócitos/química , Linfócitos/citologia , Linfócitos/metabolismo , Masculino , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase/normas , Células Tumorais Cultivadas
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