Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine mutation dominant white spotting (W) is in the proto-oncogene, c-kit. The receptor tyrosine kinase encoded by this gene has pleiotropic effects on murine development including hemopoietic cells, pigment cells, and germ cells. In this study, mutation in W homozygous mouse was identified as a single base substitution (GT----AT) at the 5'-splice donor site of the exon which encodes the transmembrane domain. Two types of aberrant exon skipping resulted from this mutation, occurred in a tissue specific manner. Either transcript lost the exon coding for transmembrane region and therefore the product might not be functional for signal transduction. Any unusual cryptic splice sites were not activated by this mutation as beta-globin gene in beta-thalassaemia. In addition, twelve base pair sequence of the 3'-end of the exon prior to the exon coding for transmembrane domain was found to be alternatively spliced. These findings should provide the genetic base for not only the receptor function but the splicing mechanism.
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PMID:Exon skipping by mutation of an authentic splice site of c-kit gene in W/W mouse. 170 86

Desferrioxamine (DFX) is an iron chelation agent widely used in the treatment of transfusional iron overload in patients with thalassaemia major and other severe refractory anaemias. DFX has been shown to induce inhibition of DNA synthesis and apoptosis in vitro; however, the molecular targets of DFX action are not well known. The c-myc proto-oncogene is involved in a number of cellular processes including proliferation, differentiation and apoptotic cell death. We have examined the expression of c-myc in peripheral blood mononuclear cells from 71 patients with homozygous beta-thalassaemia in regular transfusion and iron chelation therapy with DFX, 5 non-transfusion, non-chelation-dependent thalassaemic patients, and 15 healthy volunteers using an APAAP immunocytochemical method. We have found that mononuclear cells from thalassaemic patients receiving DFX express significantly lower levels of c-myc protein compared to control healthy volunteers or thalassaemics receiving no DFX. In vitro treatment of HL60 or K562 leukaemic cells with 100 microliters DFX also induced a rapid decrease in c-myc mRNA and protein levels, followed by apoptosis and inhibition of DNA synthesis. These effects were blocked by simultaneous addition of ferric chloride. Our data suggest that deprivation of cellular iron induces downregulation of c-myc expression in vitro and in vivo and may influence haemopoietic cell growth and survival.
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PMID:Decreased expression of c-myc oncoprotein by peripheral blood mononuclear cells in thalassaemia patients receiving desferrioxamine. 945 24

Retroviral vectors derived from gammaretroviruses or lentiviruses have now been used extensively in clinical gene therapy trials for several diseases including primary immunodeficiencies, beta thalassaemia and adrenoleukodystrophy. Their utility in this setting has been readily demonstrated by the largely favourable outcomes in recent clinical trials, however this success has been marred by the emergence of malignancies in some trials. These malignancies were a consequence of perturbation of cellular proto-oncogene expression by the integrated retroviral vectors, the process of which is referred to as 'insertional mutagenesis' (IM). In this review, the origins of our understanding of IM are reviewed and applied to the clinical gene therapy trials conducted with retroviral vectors. Old and new methods for assessing this phenomenon are discussed with a view to provide a comprehensive account of this emerging field.
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PMID:Insertional mutagenesis by retroviral vectors: current concepts and methods of analysis. 2359 Jun 35