Mutations producing beta-thalassemia reach individual gene frequencies greater than .01 in malarial-endemic regions because beta-thalassemia trait individuals have increased genetic fitness over that of normal individuals. Exon 3 of the beta-globin gene has been relatively spared as a site of common beta-thalassemia mutations. Frameshifts caused by the loss of a single nucleotide and nonsense m...

Gene therapy for hemoglobinopathies requires efficient gene transfer into hematopoietic stem cells and high-level erythroid-specific gene expression. Toward this goal, we constructed a helper-dependent adenovirus vector carrying the beta-globin locus control region (LCR) to drive green fluorescent protein (GFP) expression, whereby the LCR-GFP cassette is flanked by adeno-associated virus (AAV) ...

Human beta-globin disorders are relatively common genetic diseases cause by mutations in the beta-globin gene. Increasing the expression of the gamma-globin gene has great benefits in reducing complications associated with these diseases. The Oct-1 transcription factor is involved in the transcriptional regulation of the gamma-globin gene. The human gamma-globin genes (both Agamma and Ggamma-gl...

BACKGROUND: The thalassemic syndromes originate from mutations of the globin genes that cause, besides the characteristic clinical picture, also an increased Hb F amount. It is not yet clear if there are more factors, besides the beta globin genotype, determining the Hb F production. We have tried to find out if there are relations between total Hb and Hb F, between erythropoietin (Epo) and Hb ...

Cell type-specific gene expression is regulated by chromatin structure and the transcription factors provided by the cells. In the present study, we introduced genes packaged into chromatin into target cells using a human artificial chromosome (HAC) and analyzed regulation of gene expression. The human beta-globin gene cluster was built into an HAC (globin-HAC) and introduced into mouse embryon...

Ten patients with thalassemia intermedia with variable severity and apparent simple heterozygosis for beta0 39 C>T nonsense mutation were submitted to clinical, hematologic and molecular studies. The presence of an unknown molecular defect (silent beta-thalassemia) unlinked to the beta cluster interacting with the heterozygous beta thalassemia, was previously postulated in these families. Analy...

When introduced as part of DNA constructions containing the human beta-globin locus control region (LCR), the human embryonic beta-globin gene, epsilon, is expressed in primitive but not definitive erythroid cells of recipient transgenic mice. In contrast to this pattern, the human fetal beta-globin gene, gamma, has been shown to be expressed in both primitive and definitive erythroid cells of ...

We have used gene competition to distinguish between possible mechanisms of transcriptional activation of the genes of the human beta-globin locus. The insertion of a second beta-globin gene at different points in the locus shows that the more proximal beta gene competes more effectively for activation by the locus control region (LCR). Reducing the relative distance between the genes and the L...

Achieving long-term pancellular expression of a transferred gene at therapeutic level in a given hematopoietic lineage remains an important goal of gene therapy. Advances have recently been made in the genetic correction of the hemoglobinopathies by means of lentiviral vectors and large locus control region (LCR) derivatives. However, panerythroid beta globin gene expression has not yet been ac...