Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Genet ; 44(4): 435-9, S1-2, 2012 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-22366785

RESUMO

The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.


Assuntos
Predisposição Genética para Doença , Proteínas de Ligação a RNA/genética , Trombocitopenia/genética , Deformidades Congênitas das Extremidades Superiores/genética , Regiões 5' não Traduzidas/genética , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Variação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único , Rádio (Anatomia)/anormalidades , Alinhamento de Sequência , Análise de Sequência de DNA , Trombocitopenia/congênito , Adulto Jovem , Peixe-Zebra/genética
2.
Haematologica ; 97(1): 73-81, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21933853

RESUMO

BACKGROUND: Thrombocytopenia with absent radii syndrome is defined by bilateral radius aplasia and thrombocytopenia. Due to impaired thrombopoietin signaling there are only few bone marrow megakaryocytes and these are immature; the resulting platelet production defect improves somewhat over time. A microdeletion on chromosome 1q21 is present in all patients but is not sufficient to form thrombocytopenia with absent radii syndrome. We aimed to refine the signaling defect in this syndrome. DESIGN AND METHODS: We report an extended study of 23 pediatric and adult patients suffering from thrombocytopenia with absent radii syndrome in order to scrutinize thrombopoietin signal transduction by immunoblotting and gel electrophoretic shift assays. In addition, platelet immunotyping and reactivity were analyzed by flow cytometry. Results were correlated with clinical data including age and platelet counts. RESULTS: Two distinct signaling patterns were identified. Juvenile patients showed abrogated thrombopoietin signaling (pattern #1), which is restored in adults (pattern #2). Phosphorylated Jak2 was indicative of activation of STAT1, 3 and 5, Tyk2, ERK, and Akt, showing its pivotal role in distinct thrombopoietin-dependent pathways. Jak2 cDNA was not mutated and the thrombopoietin receptor was present on platelets. All platelets of patients expressed normal levels of CD41/61, CD49b, and CD49f receptors, while CD42a/b and CD29 were slightly reduced and the fibronectin receptor CD49e markedly reduced. Lysosomal granule release in response to thrombin receptor activating peptide was diminished. CONCLUSIONS: We show a combined defect of platelet production and function in thrombocytopenia with absent radii syndrome. The rise in platelets that most patients have during the first years of life preceded the restored thrombopoietin signaling detected at a much later age, implying that these events are uncoupled and that an unknown factor mediates the improvement of platelet production.


Assuntos
Plaquetas/metabolismo , Transdução de Sinais , Trombocitopenia/metabolismo , Trombopoetina/metabolismo , Deformidades Congênitas das Extremidades Superiores/metabolismo , Adolescente , Adulto , Fatores Etários , Linhagem Celular , Criança , Pré-Escolar , Deleção Cromossômica , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Megacariócitos/metabolismo , Contagem de Plaquetas , Rádio (Anatomia)/anormalidades , Rádio (Anatomia)/metabolismo , Receptores de Superfície Celular/metabolismo , Trombocitopenia/genética , Deformidades Congênitas das Extremidades Superiores/genética , Adulto Jovem
3.
Blood ; 114(27): 5532-40, 2009 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-19801445

RESUMO

Terminally mature megakaryocytes undergo dramatic cellular reorganization to produce hundreds of virtually identical platelets. A hallmark feature of this process is the generation of an elaborate system of branched protrusions called proplatelets. We recently identified RanBP10 as a tubulin-binding protein that is concentrated along polymerized microtubules in mature megakaryocytes. RanBP10 depletion in vitro caused the disturbance of polymerized filaments. Here we study the function of RanBP10 in vivo by generating deficient mice using a gene-trap approach. Mutant mice show normal platelet counts, and fetal liver-derived megakaryocytes reveal only slightly reduced proplatelet formation. However, ultrastructural analysis unveiled a significantly increased geometric axis ratio for resting platelets, and many platelets exhibited disorders in microtubule filament numbers and localization. Mutant mice showed a markedly prolonged bleeding time. Granule release, a process that depends on internal contraction of the microtubule marginal coil, also was reduced. Flow cytometry analysis revealed reduced expression of CD62P and CD63 after PAR4-peptide stimulation. These data suggest that RanBP10 plays an essential role in hemostasis and in maintaining microtubule dynamics with respect to both platelet shape and function.


Assuntos
Plaquetas/fisiologia , Degranulação Celular/fisiologia , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Animais , Plaquetas/citologia , Plaquetas/metabolismo , Forma Celular/genética , Forma Celular/fisiologia , Células Cultivadas , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Immunoblotting , Masculino , Megacariócitos/citologia , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Ativação Plaquetária/genética , Ativação Plaquetária/fisiologia , Agregação Plaquetária/genética , Agregação Plaquetária/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...