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1.
Hemoglobin ; 44(3): 214-217, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32605393

RESUMO

A woman completely lacking Hb A2 on the high performance liquid chromatography (HPLC) analysis, presented with a novel deletional (εγ)δß0-thal and a δ-globin gene variant. This combination causes a ß-thalassemia (ß-thal) minor phenotype. The woman was referred by a hematologist due to abnormal blood counts. Multiplex ligation-dependent probe amplification (MLPA) and microarray analysis showed a heterozygous, 177 kb long deletion that removed the locus control region enhancer plus the ε, Gγ and Aγ genes. Additional sequencing revealed a novel variant HBD: c.209G>A, p.Gly70Asp in the heterozygous state, called Hb A2-Gebenstorf. The combination of the two variants explains the lack of Hb A2 in this woman.


Assuntos
Hemoglobina A2/genética , Mutação , Talassemia beta/diagnóstico , Talassemia beta/genética , Globinas delta/genética , Alelos , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Índices de Eritrócitos , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Humanos , Fenótipo , Talassemia beta/sangue
2.
Hemoglobin ; 39(2): 144-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25786670

RESUMO

We describe two novel α2 gene mutations that result in an altered amino acid sequence. In case 1, the α2 stop codon was mutated from TAA > TTA (HBA2: c.428A > T), resulting in an α2 protein chain extension of 31 amino acids. The new hemoglobin (Hb) variant was named Hb Kinshasa for the place of origin of the patient. This patient was also a carrier of Hb S (HBB: c.20A > T), which was expressed at reduced levels, but had an otherwise normal blood count. For cases 2 and 3, an α2 frameshift mutation caused a premature α2 protein chain termination at position 133 (HBA2: c.342-345insCC). The phenotype of this mutation seems to be rather severe as judged by the pronounced microcytosis and hypochromia observed in case 2. In addition, the father of this patient (case 3) also carried a ß(0)-thalassemia (ß(0)-thal) mutation (HBB: c.118C > T).


Assuntos
Substituição de Aminoácidos , Hemoglobina A2/genética , Mutação , Fenótipo , alfa-Globinas/genética , Talassemia alfa/diagnóstico , Talassemia alfa/genética , Adulto , Anemia Falciforme/diagnóstico , Anemia Falciforme/genética , Pré-Escolar , Análise Mutacional de DNA , Índices de Eritrócitos , Feminino , Genótipo , Hemoglobina Falciforme/genética , Heterozigoto , Humanos , Masculino
3.
Hemoglobin ; 38(2): 84-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24502349

RESUMO

In two unrelated families, several newborns developed cyanosis within the first days of life. For all of them, consecutive arterial blood gas analyses showed a right shift of the saturation curve, suggesting the presence of a hemoglobin (Hb) variant. A new (G)γ-globin variant was detected, namely (G)γ105(G7)Leu → His; HBG2: c.317T > A, that we named Hb F-Brugine/Feldkirch after the place of origin of the two families. This T to A conversion results in a leucine to histidine amino acid change at codon 105 of the (G)γ-globin gene and caused a Hb variant with lowered oxygen affinity. The γ to ß switch proceeded normally.


Assuntos
Hemoglobina Fetal/genética , Hemoglobinas Anormais/genética , Mutação de Sentido Incorreto , Oxigênio/metabolismo , gama-Globinas/genética , Sequência de Bases , Ligação Competitiva , Cromatografia Líquida de Alta Pressão , Cianose/genética , Cianose/metabolismo , Análise Mutacional de DNA , Feminino , Hemoglobina Fetal/metabolismo , Hemoglobinas Anormais/metabolismo , Histidina/genética , Humanos , Recém-Nascido , Leucina/genética , Masculino , Ligação Proteica , gama-Globinas/metabolismo
5.
Hemoglobin ; 36(2): 109-13, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22384797

RESUMO

A baby girl, born at term, presented with severe cyanosis and received oxygen supplementation. Consecutive arterial blood gas analysis showed a pronounced right shift of the saturation curve, suggesting the presence of a hemoglobin (Hb) variant. A new (G)γ-globin variant was detected, namely HBG2:c.308G, which we have named Hb F-Sarajevo, the city from where the baby's parents originate. This A to C transversion exists in cis to the common (A)γ(T) and the resulting mutant Hb molecule exhibits very low oxygen affinity and cooperativity. Its analogue in the ß-globin gene is Hb Kansas [ß102(G4)Asn→Thr, AAC>ACC].


Assuntos
Cianose/genética , Hemoglobina Fetal/genética , Oxigênio/metabolismo , Mutação Puntual , gama-Globinas/genética , Sequência de Bases , Cianose/diagnóstico , Cianose/metabolismo , Análise Mutacional de DNA , Feminino , Hemoglobinas Anormais/genética , Humanos , Recém-Nascido , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
6.
Hemoglobin ; 36(2): 177-82, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22273484

RESUMO

We report three cases with very heterogeneous Hb A(2) levels caused by known chromosomal rearrangements in the ß-globin locus. These rearrangements had their breakpoints at the same region in the δ gene, leading either to the Senegalese δ(0)ß(+)-thalassemia (δ(0)ß(+)-thal) deletion or to an insertion of a δ gene, known as Anti-Lepore. One patient showed, apart from drastically increased Hb A(2) values of 17.0%, inconspicuous hematological values. He had an Anti-Lepore mutation with three copies of the δ gene, thus explaining the high Hb A(2) level. Two other patients had Hb A(2) levels in the lower borderline range and increased Hb F levels. Molecular analysis showed the Senegalese δ(0)ß(+)-thal deletion. One of them presented with an additional mild ß-thal mutation leading to ß-thal intermedia. These cases illustrate that different gene rearrangements with the same breakpoints in the δ gene can lead to different levels of Hb A(2) depending on the remaining number of δ genes.


Assuntos
Dosagem de Genes , Rearranjo Gênico/genética , Talassemia beta/genética , Globinas delta/genética , Adulto , DNA/química , DNA/genética , Quebras de DNA , Feminino , Hemoglobina Fetal/genética , Genótipo , Hemoglobina A2/genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Índice de Gravidade de Doença
7.
Hematol Rep ; 3(3): e30, 2011 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-22593821

RESUMO

We present a case of a 40-year-old female from Turkey, who was referred to our outpatient clinic for an undetermined thalassemia and sickle cell trait. At first consultation hemoglobin was decreased (71 g/L) with microcytosis (MCV 55.1 fL), and hypochromia (MCHC 239 g/L). The patient had severe iron deficiency. Brilliant cresyl blue staining showed >50% of the erythrocytes with typical Hemoglobin H (HbH) inclusions. High-performance liquid chromatography (HPLC) revealed normal levels of HbA(2) and Hemoglobin F (HbF), and additionally a hemoglobin S (19%). Molecular diagnostics revealed the mutations α2 IVS-I donor site -5nt and a -- MED II deletion in the alpha gene complex and confirmed the heterozygote mutation of the beta-gene at codon 6 (HBB:c.20A>T; HbS). In conclusion, we present an extremely rare combination of HbH disease and sickle cell trait. This combination may explain the mild form of the HbH disease, with moderate anemia, splenomegaly but iron deficiency, rather than iron overload, as usually observed in HbH disease.

8.
Nat Immunol ; 11(11): 1030-8, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20935648

RESUMO

The potent tumoricidal activity of interleukin 12 (IL-12) is thought to be mediated by the activation and polarization of natural killer (NK) cells and T helper type 1 (T(H)1) cells, respectively. By systematic analysis of the IL-12-induced immune response to subcutaneous melanoma (B16), we found that tumor suppression was mediated independently of T lymphocytes or NK cells. IL-12 initiated local antitumor immunity by stimulating a subset of NKp46(+) lymphoid tissue-inducer (LTi) cells dependent on the transcription factor RORγt. The presence of these NKp46(+) LTi cells induced upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte invasion. Thus, this innate cell type is responsive to IL-12 and is a powerful mediator of tumor suppression.


Assuntos
Interleucina-12/imunologia , Tecido Linfoide/imunologia , Melanoma/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Animais , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Tumorais Cultivadas
9.
Int J Cancer ; 122(7): 1585-91, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18041742

RESUMO

NY-BR-1 is a differentiation antigen and a potential target for cancer immunotherapy. Its mRNA expression is restricted to breast, testis, prostate and breast cancer by RT-PCR. In this study, we correlated NY-BR-1 protein and mRNA expression on tissue microarrays of mammary, prostatic and testicular malignancies using immunohistochemistry and in situ hybridization with probes for exon 4-7 and 30-33. NY-BR-1 mRNA was confined to primary spermatocytes, suggesting a role in spermatogenesis. Exon 4-7 and 30-33 were equally expressed this cell type. However, NY-BR-1 was absent in all germ cell tumours analyzed (n = 475) and present in one of 56 (2%) prostate carcinomas. In breast, NY-BR-1 mRNA expression was detected in 307 of 442 (70%) primary carcinomas, with strong correlation to its protein expression (p < 0.0001). mRNA expression was significantly stronger and more frequently detected by the exon 30-33 probe than by the exon 4-7 probe (70% vs. 35%, p < 0.0001), indicating the presence of alternative splice variants that lack 5-prime sequences. A similar restricted mRNA pattern was also observed in the normal breast epithelium. NY-BR-1 protein and mRNA correlated significantly with estrogen receptor alpha (ER alpha) protein expression (p < 0.0001), with stronger association to NY-BR-1 mRNA than protein (odds ratio 7.7 compared to 4.6). We identified 4 estrogen response elements (ERE)-like sequences nearby the promoter region, suggesting that NY-BR-1 transcription might be controlled by ER alpha. Accordingly, analysis of matching pairs of primary tumors with their recurrences showed a marked decrease of NY-BR-1 expression in recurrences after tamoxifen treatment (p < 0.0001).


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Neoplasias da Mama/imunologia , Mama/imunologia , Neoplasias da Próstata/imunologia , Receptores de Estrogênio , Elementos de Resposta , Neoplasias Testiculares/imunologia , Testículo/imunologia , Antígenos de Neoplasias/genética , Antineoplásicos Hormonais/uso terapêutico , Moduladores de Receptor Estrogênico/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , RNA Mensageiro/análise , Receptores de Estrogênio/metabolismo , Tamoxifeno/uso terapêutico
10.
Genes Dev ; 16(14): 1828-38, 2002 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12130542

RESUMO

In the embryonic midgut of Drosophila, Wingless (Wg) signaling elicits threshold-specific transcriptional response, that is, low-signaling levels activate target genes, whereas high-signaling levels repress them. Wg-mediated repression of the HOX gene Ultrabithorax (Ubx) is conferred by a response sequence within the Ubx B midgut enhancer, called WRS-R. It further depends on the Teashirt (Tsh) repressor, which acts through the WRS-R without binding to it. Here, we show that Wg-mediated repression of Ubx B depends on Brinker, which binds to the WRS-R. Furthermore, Brinker blocks transcriptional activation by ubiquitous Wg signaling. Brinker binds to Tsh in vitro, recruits Tsh to the WRS-R, and we find mutual physical interactions between Brinker, Tsh, and the corepressor dCtBP. This suggests that the three proteins may form a ternary repressor complex at the WRS-R to quench the activity of the nearby-bound dTCF/Armadillo transcription complex. Finally, brinker and tsh produce similar mutant phenotypes in the ventral epidermis, and double mutants mimic overactive Wg signaling in this tissue. This suggests that Brinker may have a widespread function in antagonizing Wg signaling.


Assuntos
Proteínas de Homeodomínio , Proteínas de Insetos/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Oxirredutases do Álcool , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sistema Digestório/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Epiderme/embriologia , Epiderme/metabolismo , Proteínas de Insetos/genética , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteína Wnt1
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