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2.
J Clin Invest ; 128(9): 3957-3975, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-29969437

RESUMO

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

4.
J Allergy Clin Immunol ; 141(3): 1060-1073.e3, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28629746

RESUMO

BACKGROUND: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. OBJECTIVE: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. RESULTS: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin ß receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.

5.
Proc Natl Acad Sci U S A ; 113(51): E8277-E8285, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930337

RESUMO

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.


Assuntos
Infecções Bacterianas/imunologia , Candidíase/imunologia , Micoses/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Alelos , Candida , Membrana Celular , Criança , Pré-Escolar , Saúde da Família , Feminino , Fibroblastos/metabolismo , Genes Recessivos , Estudo de Associação Genômica Ampla , Células HEK293 , Homozigoto , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Interleucina-17/metabolismo , Masculino , Mutação , Fases de Leitura Aberta , Linhagem , Receptores de Interleucina-17/metabolismo , Pele/microbiologia , Linfócitos T/citologia
7.
Am J Med Genet A ; 170A(1): 189-94, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26360803

RESUMO

Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra-cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single-agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning-Feuerstein-Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most-druggable targets.


Assuntos
Adenoma de Glândula Sudorípara/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias das Glândulas Sudoríparas/genética , Adenoma de Glândula Sudorípara/tratamento farmacológico , Astrocitoma/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Olho/patologia , Anormalidades do Olho/genética , Humanos , Indóis/uso terapêutico , Lactente , Mosaicismo , Nevo Sebáceo de Jadassohn/genética , Nascimento Prematuro , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Neoplasias das Glândulas Sudoríparas/tratamento farmacológico , Vemurafenib
8.
Pediatr Int ; 56(5): e55-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25336010

RESUMO

Mesenchymal chondrosarcoma (MC) is an extremely rare subtype of chondrosarcoma that has a small round-cell sarcoma with focal cartilaginous differentiation, often with a pericytomatous vascular pattern. The non-cartilaginous components are usually dominant, and such lesions might be confused with other small round-cell tumors. Recently, a tumor-specific HEY1-NCOA2 fusion gene was identified in MC. Here we report the case of a 9-year-old boy who was diagnosed with MC by detection of HEY1-NCOA2 fusion signals in almost 50% of tumor cells in tissue sections on fluorescence in situ hybridization (FISH). In this way, the tumor was definitively diagnosed as MC. This case suggests that the detection of the HEY1-NCOA2 fusion gene on FISH is of diagnostic value for MC.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/genética , Proteínas de Ciclo Celular/genética , Condrossarcoma Mesenquimal/diagnóstico , Condrossarcoma Mesenquimal/genética , Fusão Gênica , Hibridização in Situ Fluorescente , Coativador 2 de Receptor Nuclear/genética , Tíbia , Criança , Humanos , Masculino
9.
Biochem Biophys Res Commun ; 447(2): 346-51, 2014 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-24726647

RESUMO

Notch1 mutations are found in more than 50% of human T cell acute lymphoblastic leukemia (T-ALL) cells. However, the functions of Notch1 for human T cell development and leukemogenesis are not well understood. To examine the role of Notch1, human hematopoietic stem cells (HSCs), which had been transduced with a constitutively active form of Notch1 (ICN1), were transplanted into severely immunodeficient NOD/Shi-scid-IL2rγ(null) (NOG) mice. We found that the great majority of the ICN1-expressing hematopoietic cells in the bone marrow expressed surface markers for T cells, such as CD3, CD4, and CD8, and that this T cell development was independent of the thymus. Accordingly, phenotypically mature CD8(+) single positive (SP) T cells were observed in the spleen. Furthermore, T-ALL developed in one NOG recipient mouse out of 26 that had been secondary transferred with the T cells developed in the first NOG mice. These results indicate that Notch1 signaling in HSCs promotes CD8(+) SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation.


Assuntos
Linfócitos T CD8-Positivos/patologia , Carcinogênese , Células-Tronco Hematopoéticas/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/genética , Baço/patologia
11.
Cancer Sci ; 105(3): 359-62, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24344754

RESUMO

We report on a 24-year-old woman who was diagnosed as having Maffucci syndrome with anaplastic astrocytoma. We analyzed the IDH1 and IDH2 mutations of enchondroma, hemangioma and anaplastic astrocytoma tissues and the same somatic mosaic mutation in IDH2 gene was identified in all these tissues. In addition, we identified additional mutation of the TP53 gene in anaplastic astrocytoma tissue but not in other benign tumors. This is the first report of the detection of an identical IDH2 mutation in multiple tissues and TP53 mutation in anaplastic astrocytoma in a patient with Maffucci syndrome. This case is unique and supports the IDH2-dependent genetic pathway and second-hit model for gliomagenesis.


Assuntos
Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Encondromatose/genética , Isocitrato Desidrogenase/genética , Proteína Supressora de Tumor p53/genética , Astrocitoma/genética , Astrocitoma/terapia , Sequência de Bases , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Análise Mutacional de DNA , Evolução Fatal , Feminino , Hemangioma/diagnóstico , Hemangioma/genética , Humanos , Mutação de Sentido Incorreto , Radiografia , Adulto Jovem
12.
Biochem Biophys Res Commun ; 443(2): 351-6, 2014 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-24246674

RESUMO

Hepatocyte growth factor (HGF)-regulated tyrosine kinase substrate (Hrs) is a vesicular sorting protein that functions as one of the endosomal-sorting proteins required for transport (ESCRT). Hrs, which binds to ubiquitinated proteins through its ubiquitin-interacting motif (UIM), contributes to the lysosomal transport and degradation of ubiquitinated membrane proteins. However, little is known about the relationship between B-cell functions and ESCRT proteins in vivo. Here we examined the immunological roles of Hrs in B-cell development and functions using B-cell-specific Hrs-deficient (Hrs(flox/flox);mb1(cre/)(+):Hrs-cKO) mice, which were generated using a cre-LoxP recombination system. Hrs deficiency in B-cells significantly reduced T-cell-dependent antibody production in vivo and impaired the proliferation of B-cells treated in vitro with an anti-IgM monoclonal antibody but not with LPS. Although early development of B-cells in the bone marrow was normal in Hrs-cKO mice, there was a significant decrease in the number of the peripheral transitional B-cells and marginal zone B-cells in the spleen of Hrs-cKO mice. These results indicate that Hrs plays important roles during peripheral development and physiological functions of B lymphocytes.


Assuntos
Linfócitos B/citologia , Linfócitos B/fisiologia , Endocitose/fisiologia , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Endossomos/enzimologia , Fator de Crescimento de Hepatócito/metabolismo , Fosfoproteínas/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Especificidade por Substrato
13.
Eur J Haematol ; 91(3): 242-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23734904

RESUMO

BACKGROUND: Epstein-Barr virus (EBV)-infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial. PATIENTS AND METHODS: We retrospectively analyzed five patients with CAEBV treated with reduced-intensity conditioning (RIC) consisted of fludarabine, cyclophosphamide, and low-dose total-body irradiation followed by allogeneic bone marrow transplantation in a single institute. Only one of five patients received chemotherapy prior to transplantation. We analyzed EBV-infected cells in a patient whose EBV load increased after HSCT by T-cell repertoire assay, separation of T-cell subpopulations, in situ hybridization and microsatellite analysis. RESULTS: All five patients achieved engraftment, complete chimera, and eradication of EBV load. All patients have been alive without any serious regimen-related toxicity for more than 16 months following HSCT. However, one patient transplanted from HLA-matched sibling donor developed clonal proliferation of CD4+ Vß3+ T cells caused by monoclonal EBV infection on day 99 after transplantation. Further analysis revealed that the CD4+ Vß3+ T cells selectively harbored EBV genome, and these infected cells were derived from donor T cells. CONCLUSIONS: Allogeneic HSCT with RIC is a safe and effective treatment for better overall survival and less regimen-related toxicity in patients with CAEBV. Our first pediatric case reported in the literature suggests that we should consider the possibility of persistent EBV infection in donor T cells as well as the relapse in recipient cells if EBV load increases after allogeneic HSCT.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4 , Subpopulações de Linfócitos/virologia , Condicionamento Pré-Transplante , Adolescente , Antígenos CD4/metabolismo , Criança , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/transmissão , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Humanos , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Doadores de Tecidos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
14.
Int J Hematol ; 98(2): 237-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23702915

RESUMO

Autoimmune hemolytic anemia (AIHA) is a rare disease in infants, for which steroids are recognized as a first-line therapy for patients. Rituximab, a humanized monoclonal antibody raised against CD20, has been used in the treatment of autoimmune diseases, including AIHA, in adults and children. Due to limited follow-up study of the use of rituximab in the treatment for AIHA, its long-term efficacy, adverse effects, and immunological reconstitution of B cells have not been fully evaluated in infants. Here, we report a 3-month-old female patient with refractory AIHA, who was successfully treated with rituximab. Hemolytic anemia improved rapidly, and there were no severe adverse effects caused by rituximab. After 4.5 months following rituximab treatment, peripheral B cells were gradually reconstituted and required no intravenous immunoglobulin replacement thereafter. The patient has remained disease-free for more than 30 months without any additional treatment. This case suggests that rituximab may be a valuable therapeutic option, given its efficacy and minimal adverse effects in infants with therapy-resistant AIHA.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais Murinos/administração & dosagem , Antineoplásicos/administração & dosagem , Anemia Hemolítica Autoimune/diagnóstico , Feminino , Humanos , Lactente , Indução de Remissão , Rituximab , Fatores de Tempo
15.
Eur J Pediatr ; 172(7): 953-7, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23443156

RESUMO

Mutations in genes critical for surfactant metabolism, including surfactant protein C (SP-C) and ABCA3, are well-recognized causes of interstitial lung disease. Recessive mutations in ABCA3 were first attributed to fatal respiratory failure in full-term neonates, but they are also increasingly being recognized as a cause of respiratory disorders with less severe phenotypes in older children and also adults. Here, we report a 20-month-old boy with interstitial lung disease caused by two distinct ABCA3 mutations. Initial treatment with methylprednisolone was unsuccessful, but the additional administration of hydroxychloroquine was effective. The family history revealed that the patient's older brother had died of idiopathic interstitial lung disease at 6 months of age, suggesting a genetic etiology of the disease. Sequence analyses of SP-C and ABCA3 genes were performed using DNA samples from the patient himself, his parents, and his brother. These analyses revealed novel compound heterozygous mutations in the coding exons of ABCA3 in both the patient and his brother: c.2741A > G, of paternal origin, and c.3715_3716insGGGGGG, of maternal origin. Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hidroxicloroquina/uso terapêutico , Doenças Pulmonares Intersticiais/genética , Proteínas Associadas a Surfactantes Pulmonares/genética , Evolução Fatal , Heterozigoto , Humanos , Lactente , Doenças Pulmonares Intersticiais/tratamento farmacológico , Masculino , Mutação , Fenótipo , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Análise de Sequência de DNA , Irmãos
16.
PLoS One ; 7(6): e37892, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22745659

RESUMO

Mixed-lineage-leukemia (MLL) fusion oncogenes are intimately involved in acute leukemia and secondary therapy-related acute leukemia. To understand MLL-rearranged leukemia, several murine models for this disease have been established. However, the mouse leukemia derived from mouse hematopoietic stem cells (HSCs) may not be fully comparable with human leukemia. Here we developed a humanized mouse model for human leukemia by transplanting human cord blood-derived HSCs transduced with an MLL-AF10 oncogene into a supra-immunodeficient mouse strain, NOD/Shi-scid, IL-2Rγ(-/-) (NOG) mice. Injection of the MLL-AF10-transduced HSCs into the liver of NOG mice enhanced multilineage hematopoiesis, but did not induce leukemia. Because active mutations in ras genes are often found in MLL-related leukemia, we next transduced the gene for a constitutively active form of K-ras along with the MLL-AF10 oncogene. Eight weeks after transplantation, all the recipient mice had developed acute monoblastic leukemia (the M5 phenotype in French-American-British classification). We thus successfully established a human MLL-rearranged leukemia that was derived in vivo from human HSCs. In addition, since the enforced expression of the mutant K-ras alone was insufficient to induce leukemia, the present model may also be a useful experimental platform for the multi-step leukemogenesis model of human leukemia.


Assuntos
Leucemia/metabolismo , Proteína de Leucina Linfoide-Mieloide/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Animais , Southern Blotting , Modelos Animais de Doenças , Citometria de Fluxo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia/genética , Camundongos , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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