Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Blood Adv ; 4(8): 1760-1769, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.

3.
Haematologica ; 103(6): 949-958, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29599205

RESUMO

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure disorder linked predominantly to ribosomal protein gene mutations. Here the European DBA consortium reports novel mutations identified in the RPL15 gene in 6 unrelated individuals diagnosed with DBA. Although point mutations have not been previously reported for RPL15, we identified 4 individuals with truncating mutations p.Tyr81* (in 3 of 4) and p.Gln29*, and 2 with missense variants p.Leu10Pro and p.Lys153Thr. Notably, 75% (3 of 4) of truncating mutation carriers manifested with severe hydrops fetalis and required intrauterine transfusions. Even more remarkable is the observation that the 3 carriers of p.Tyr81* mutation became treatment-independent between four and 16 months of life and maintained normal blood counts until their last follow up. Genetic reversion at the DNA level as a potential mechanism of remission was not observed in our patients. In vitro studies revealed that cells carrying RPL15 mutations have pre-rRNA processing defects, reduced 60S ribosomal subunit formation, and severe proliferation defects. Red cell culture assays of RPL15-mutated primary erythroblast cells also showed a severe reduction in cell proliferation, delayed erythroid differentiation, elevated TP53 activity, and increased apoptosis. This study identifies a novel subgroup of DBA with mutations in the RPL15 gene with an unexpected high rate of hydrops fetalis and spontaneous, long-lasting remission.


Assuntos
Anemia de Diamond-Blackfan/complicações , Anemia de Diamond-Blackfan/genética , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/etiologia , Mutação , Complicações Hematológicas na Gravidez , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/terapia , Apoptose/genética , Biomarcadores , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células , Análise Mutacional de DNA , Índices de Eritrócitos , Feminino , Genes p53 , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Linhagem , Fenótipo , Gravidez , Biossíntese de Proteínas
4.
Thromb Haemost ; 106(3): 475-83, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21800012

RESUMO

The bleeding disorder Bernard-Soulier syndrome (BSS) is caused by mutations in the genes coding for the platelet glycoprotein GPIb/IX receptor. The septin SEPT5 is important for active membrane movement such as vesicle trafficking and exocytosis in non-dividing cells (i.e. platelets, neurons). We report on a four-year-old boy with a homozygous deletion comprising not only glycoprotein Ibß (GP1BB) but also the SEPT5 gene, located 5' to GP1BB. He presented with BSS, cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. The homozygous deletion of GP1BB and SEPT5, which had been identified by PCR analyses, was confirmed by Southern analyses and denaturing HPLC (DHPLC). The parents were heterozygous for this deletion. Absence of GPIbß and SEPT5 proteins in the patient's platelets was illustrated using transmission electron microscopy. Besides decreased GPIb/IX expression, flow cytometry analyses revealed impaired platelet granule secretion. Because the bleeding disorder was extremely severe, the boy received bone marrow transplantation (BMT) from a HLA-identical unrelated donor. After successful engraftment of BMT, he had no more bleeding episodes. Interestingly, also his mental development improved strikingly after BMT. This report describes for the first time a patient with SEPT5 deficiency presenting with cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect.


Assuntos
Síndrome de Bernard-Soulier/terapia , Transplante de Medula Óssea , Proteínas de Ciclo Celular/genética , Fator IX/genética , Septinas/genética , Síndrome de Bernard-Soulier/genética , Síndrome de Bernard-Soulier/patologia , Síndrome de Bernard-Soulier/fisiopatologia , Plaquetas/metabolismo , Plaquetas/patologia , Pré-Escolar , Intervalo Livre de Doença , Exocitose/genética , Homozigoto , Humanos , Tolerância Imunológica , Masculino , Malformações do Desenvolvimento Cortical , Microscopia Eletrônica de Transmissão , Neurônios/metabolismo , Neurônios/patologia , Via Secretória/genética , Vesículas Secretórias/metabolismo , Deleção de Sequência/genética
5.
Ann Hematol ; 89 Suppl 1: 11-7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20449748

RESUMO

Immune thrombocytopenia (ITP) is a common disorder in children and adults. In a patient with newly diagnosed ITP, the treatment strategy is relatively well defined. Second-line treatments are more controversial, and the management of chronic ITP is even more so. During the 3rd ICIS Expert Meeting on Consensus and Development of Strategies in ITP, held in Basel on September 3-5, 2009, a group of experts were tasked with reaching a consensus on some frequently asked questions relating to diagnosis and management of children and adults with chronic ITP. The content of this article is designed to provide a practical support to trained haematologists in their care of patients with chronic ITP.


Assuntos
Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Adulto , Antígenos de Plaquetas Humanas/imunologia , Autoimunidade , Medula Óssea/imunologia , Medula Óssea/fisiopatologia , Criança , Doença Crônica , Humanos , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/fisiopatologia
6.
Hamostaseologie ; 29(2): 184-6, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19404516

RESUMO

The genotype-phenotype relationship of compound heterozygous factor X deficiency in a young girl with severe factor X deficiency and bleeding symptoms is characterized. We identified a novel deletion of exon 6 and a missense mutation (c.856G>A, Val286Met) in exon 7 of the F10 gene leading to a compound heterozygous state and causing severe factor X deficiency. Therapeutic options for patients with symptomatic factor X deficiency are demonstrated.


Assuntos
Deficiência do Fator X/genética , Fator X/genética , Éxons , Deficiência do Fator X/diagnóstico , Feminino , Deleção de Genes , Genótipo , Hemorragia/etiologia , Humanos , Lactente , Mutação de Sentido Incorreto , Fenótipo
7.
Genes Chromosomes Cancer ; 45(8): 731-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16646086

RESUMO

The t(7;12)(q36;p13) is a recurrent translocation involving the ETV6/TEL gene (12p13) and a heterogeneous breakpoint at 7q36. A fusion transcript between HLXB9 and ETV6 in AML with t(7;12) is occasionally found. To study the incidence of t(7;12) in infant and childhood acute leukemia, we screened 320 cases <36 months using FISH. Additionally, 28 pediatric cases >36 months with cytogenetic breakpoints at 12p and 7q were investigated. We studied the presence of an HXLB9-ETV6 fusion transcript and quantified the expression of various genes located in the 7q36 breakpoint region. In total, six AML patients carried the t(7;12) of which five were infants and one child of 18 months. Only one out of 99 infant ALL patients harbored the t(7;12). No t(7;12) was found in older children with AML or ALL. AML patients carrying a t(7;12) had a poor outcome with a 3-year EFS of 0%. A fusion of HLXB9 to ETV6 was found in four AML cases with t(7;12). The 7q36 genes NOM1, LMBR1, RNF32, and SHH were equally expressed among t(7;12)-positive AML versus t(7;12)-negative AML, t(7;12)-negative ALL, or normal bone marrow. However, the HLXB9 expression was highly increased in t(7;12)-positive cases, including those with an HLXB9-ETV6 fusion. We conclude that the t(7;12) is almost exclusively present in infant AML and covers 30% of infant AML, while it is extremely rare in infant ALL and older children. The t(7;12) is associated with a poor outcome and an ectopic expression of HLXB9 is commonly involved in this genetic subtype of leukemia.


Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 7 , Proteínas de Homeodomínio/genética , Leucemia Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Fatores de Transcrição/genética , Translocação Genética , Doença Aguda , Pré-Escolar , Quebra Cromossômica , Estudos de Coortes , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Masculino , Modelos Genéticos , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismo
8.
Thromb Haemost ; 91(5): 959-66, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15116257

RESUMO

Septins are a family of GTP-binding proteins, which are essential for active membrane movement such as cytokinesis and vesicle trafficking. In non-dividing cells (such as platelets and neurons) septins are implicated in exocytosis. Platelets from a SEPT5 knockout mouse showed an altered serotonin secretion and platelet aggregation, suggesting that SEPT5 is involved in secretion in platelets. Septins form complexes consisting of multiple septin polypeptides. Using the yeast two-hybrid system we had demonstrated that SEPT5 partners with SEPT8. The aim of this study was to identify other interaction partners of the human platelet septin SEPT8. Using the yeast two-hybrid system with SEPT8 as bait protein we identified the human septin SEPT4 as an interaction partner of SEPT8. The interaction between SEPT4 and SEPT8 was confirmed by immunoprecipitation. Expression analysis revealed that SEPT4 is also expressed in human platelets. Thus, SEPT4 is the third described platelet septin besides SEPT5 and SEPT8. Transmission electron microscopy of platelets revealed that SEPT8 and SEPT4 are localized surrounding alpha-granules (as it had been shown for the septin SEPT5) suggesting that the three septins may be components of the septin complex in platelets and contribute in such a way to platelet biology. Activation of platelets by agonists resulted in the translocation of SEPT4 and SEPT8 to the platelet surface indicating a possible functional role of these proteins in platelet granular secretion.


Assuntos
Plaquetas/química , Proteínas do Citoesqueleto/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Membrana/metabolismo , Mapeamento de Interação de Proteínas , Plaquetas/fisiologia , Plaquetas/ultraestrutura , Proteínas do Citoesqueleto/fisiologia , GTP Fosfo-Hidrolases/fisiologia , Biblioteca Gênica , Humanos , Substâncias Macromoleculares , Proteínas de Membrana/fisiologia , Ligação Proteica , Transporte Proteico , Vesículas Secretórias/química , Septinas , Técnicas do Sistema de Duplo-Híbrido
9.
Gene ; 312: 313-20, 2003 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-12909369

RESUMO

SEPT8 (KIAA0202) is a member of the highly conserved septin family. Septins are membrane-associated GTPases which are involved in cytokinesis and cellular morphogenesis. Using the yeast two-hybrid system and the glutathione-S-transferase pull-down assay we previously had identified the SEPT8 (KIAA0202) as interaction partner of the human septin SEPT5 (cell division cycle related-1, CDCrel-1). Since the complete cDNA sequence of the human septin SEPT8 (KIAA0202) was not known at that time, we isolated new 5' and 3' cDNA sequence of SEPT8 (KIAA0202) by screening three different cDNA libraries. In addition, we performed the characterization of SEPT8 (KIAA0202) and identified new splice variants of SEPT8 (KIAA0202). The expression pattern of SEPT8 (KIAA0202) and its interaction partner SEPT5 (CDCrel-1) is illustrated.


Assuntos
Proteínas de Ciclo Celular , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Processamento Alternativo , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , DNA Complementar/química , DNA Complementar/genética , DNA Complementar/isolamento & purificação , Éxons , Feminino , GTP Fosfo-Hidrolases/metabolismo , Regulação Enzimológica da Expressão Gênica , Genes/genética , Humanos , Íntrons , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Septinas , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos
10.
FEBS Lett ; 519(1-3): 169-72, 2002 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-12023038

RESUMO

Septins are evolutionary conserved cytoskeletal GTPases forming heteropolymer complexes involved in cytokinesis and other cellular processes. CDCrel-1 (cell division cycle related-1) is a recently cloned and characterized human septin which is highly expressed in non-dividing cells, such as neurons. Using a yeast two-hybrid system we demonstrate that CDCrel-1 partners with another uncharacterized human septin, KIAA0202. The interaction of CDCrel-1 and KIAA0202 was confirmed in the human leukemia cell line K-562 using pull-down assays with a KIAA0202-glutathione S-transferase fusion protein and by immunoprecipitation of the CDCrel-1-KIAA0202 complex with an anti-KIAA0202 antibody. Expression studies of the two human septins revealed a concomitant expression of both proteins in certain cells.


Assuntos
Proteínas de Ciclo Celular , GTP Fosfo-Hidrolases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Anticorpos/metabolismo , Plaquetas/metabolismo , Northern Blotting , Western Blotting , Encéfalo/metabolismo , GTP Fosfo-Hidrolases/genética , Expressão Gênica , Glutationa Transferase/genética , Humanos , Células K562 , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/genética , Testes de Precipitina , Ligação Proteica/fisiologia , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Septinas , Técnicas do Sistema de Duplo-Híbrido
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA