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

Core promoters are defined by the presence of either a TATA box at approximately 30 base pairs upstream of the transcriptional start site (+1) and/or an initiator element centered around the +1 site. The prevalence, function, and significance of the various combinations of core promoter elements are as yet unclear. We describe here the identification and characterization of an initiator element in the TATA-containing human beta-globin promoter. Mutagenesis of the beta-globin initiator element at positions +2/+3 and +4/+5 abrogates transcription in a heterologous construct. Interestingly, we have found a beta-globin initiator binding activity in nuclear extracts whose presence or absence correlates with function of the beta-globin initiator. Accordingly, this binding activity may be part of the machinery required for beta-globin initiator-dependent transcription. Our analysis further describes a previously uncharacterized beta-thalassemia mutation at the +1 site as a mutation that decreases beta-globin initiator activity. Finally, consistent with other initiator elements, the beta-globin initiator requires a TFIID-containing fraction for in vitro activity. Thus, the human beta-globin promoter contains an initiator element whose function, as revealed by a beta-thalassemia mutation, is of physiological relevance.
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PMID:A functional initiator element in the human beta-globin promoter. 749 3

Naturally occurring deletion mutations within the human beta-globin cluster lead to specific, phenotypically discrete syndromes (i.e., delta beta-thalassemias and hereditary persistence of fetal hemoglobin, HPFH), characterized by increased production of fetal hemoglobin in adult life. We have previously characterized an enhancer element, which is juxtaposed to the fetal G gamma-gene, by means of a deletion first described in a Thai family. To obtain further insights into the mechanisms involved in this deletion, we have now characterized several of its novel features. Following amplification by the polymerase chain reaction and sequencing of the 1.5-kb bridging fragment, we have shown that the 5' breakpoint of the deletion occurs 1260 bp 3' of the fetal G gamma-globin gene, whereas the 3' breakpoint lies 521 bp upstream of the EcoRI site of the enhancer element and 2845 bp upstream of the 3' breakpoint of the Chinese (A gamma delta beta) zero-thalassemia deletion. The total length of the deletion is 101 kb, which resembles that of HPFH-1 and HPFH-2 deletions and a set of two gamma delta beta-thalassemia deletions. Our data further support the hypothesis that these sets of large deletions with almost identical lengths are generated via the loss of a complete chromatin loop. To elucidate further the mechanisms leading to the deletion, we have sequenced the novel 0.5-kb region residing immediately 3' to the breakpoint and shown that it contains putative binding sites for several transcription factors, such as HNF-1, AP-1, and TFIID. Sequence comparison of the deletion breakpoints reveals no junctional homology, indicating an end-to-end joining of blunted ends; a pair of 7-nt complementary repeats adjacent to a set of a direct CCCT repeat flanks the breakpoints. This limited homology constitutes a frequent characteristic of a non-homologous recombination mechanism. All these features of the HPFH-6 deletion suggest that this mutation has resulted from a non-homologous recombination event.
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PMID:Molecular cloning of the breakpoints of the hereditary persistence of fetal hemoglobin type-6 (HPFH-6) deletion and sequence analysis of the novel juxtaposed region from the 3' end of the beta-globin gene cluster. 927 69