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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two novel beta-thalassemia mutations are described. The first mutation, found in an Italian family, is a G----A substitution in nucleotide (nt) +22 relative to the beta-globin gene Cap site. This mutation creates a cryptic ATG initiation codon, the utilization of which for translation would result in premature termination 36 bp 3' downstream. The second mutation, found in an Irish family, is a T----C substitution in nt +1570, or 12 bp 5' upstream of the AATAAA polyadenylation signal in the 3' noncoding region. It is postulated that this mutation leads to destabilization of the encoded beta-globin mRNA.
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PMID:Two novel beta-thalassemia mutations in the 5' and 3' noncoding regions of the beta-globin gene. 151 49

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

The large degree of phenotypic heterogeneity of thalassemia can now be related to the underlying genomic defects. This information has accumulated rapidly over the last years through the recent advances in molecular technology. The list of main types of thalassemia (alpha or beta) that can be differentiated includes several gene deletions (complete or partial) and point mutations (or very short deletions). These occur within the genes or across the flanking DNA sequences and apparently interfere with the expression of these genes. From a quantitative point of view, the severity of the condition is directly related to the amount of functional globin chain mRNA which is made available to the ribosomes; this may vary from zero (gene deletions, frameshift, non-sense mutations or mutations at the splice-junction nucleotides) to very little (mostly hnRNA processing mutants) or to slightly subnormal (transcriptional mutants, mutations resulting in cryptic site activation or in defective cleavage of the poly-A tail). A few hyper-unstable globin chains also produce a thalassemic phenotype. This pattern is straightforward in the alpha-thalassemias. In the beta-thalassemias, the decreased beta-chain synthesis reflects the available mRNA, but the phenotypic expression depends also on the ability of the patient to reactivate gamma-chain synthesis and complement the red cell content with hemoglobin F.
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PMID:Thalassemia: genotypes and phenotypes. 203 76

Nucleotide sequence of the exon-intron junction in human alpha-globin gene was analyzed by quantification method proposed previously. Using sample score of 9-nucleotide sequence at 5'-splice site, we examined strength of the splice signal. We further studied a mutant of alpha-thalassemia, where pentanucleotide deletion occurs around 5'-splice junction of the first intron. This mutation abolishes the normal 5'-splice site completely, but activates a cryptic site lying in the first exon. Such a behaviour was well explained in terms of our sample scoring scheme.
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PMID:Quantification analysis of human alpha-globin gene. Mutation in 5'-splice junction sequence and alpha-thalassemia. 210 9

Concerning the signals which direct excision of introns from mRNA precursors in higher eukaryotic genes, consensus 9-nucleotide sequence, (CA)AG/GT(AG)AGT, has been proposed with the 5'-splice site, but actual 5'-splice site sequences differ from it in a greater or lesser degree. We analyzed 5'-splice site sequence of human beta-globin gene by quantification method (categorical discriminant analysis) proposed previously. Analysis of 13-nucleotide sequences and deleted sequences showed that 9-nucleotide sequences in the consensus region are almost sufficient to define 5'-splice signal. To confirm this view, we examined a number of beta-globin mutant genes, where nucleotide changes occur at the authentic 5'-splice site of the first intron and cause beta-thalassemia phenotype. Our method could explain why such mutations abolish the 5'-splice site and cryptic 5'-splice sites are activated.
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PMID:Quantification analysis of 5'-splice signal sequences in mRNA precursors. Mutations in 5'-splice signal sequence of human beta-globin gene and beta-thalassemia. 224

A G to T transversion at the fifth nucleotide of the first intervening sequence (IVS-1) of the beta-globin gene has been identified in cloned beta-thalassemia genes of two unrelated individuals, one of Mediterranean and the other of Anglo Saxon ancestry. In each patient the mutation was present in a different beta globin gene framework, defined by intragenic restriction site polymorphisms, thereby suggesting the occurrence of independent mutations. The study of the RNA products of one of these cloned genes, after transfer and transient expression in HeLa cells, showed partial inactivation of the normal donor splice site of IVS-1 and activation of two major and one minor cryptic splice sites. Only one of the two major cryptic sites was utilized in a cell-free splicing extract. The effects of this mutation on messenger RNA (mRNA) splicing are similar to that of another beta thalassemia gene with a G to C transition at the same position.
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PMID:A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. 243 49

The specificity of antibodies bound to senescent red cells has been assessed by elution analysis with various carbohydrates. A large proportion of these antibodies bound to normal senescent red cells and some pathologic red cells display a specificity to alpha-galactosyl carbohydrates. Anti-Gal (anti-alpha-galactosyl antibody) constitutes as much as 1% of circulating IgG in humans; it interacts specifically with Gal alpha 1----3Gal glycosidic structures. This study suggests that a cryptic B-like Gal alpha----3 Gal epitope is exposed on red cells as they age in the circulation and subsequently binds the anti-Gal antibody. Furthermore, it was hypothesized that, in some hemolytic disorders, pathologic alterations in the red cells may lead to premature exposure of this antigen, and, hence, to increased extravascular lysis observed in such diseases as beta-thalassemia and sickle cell anemia.
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PMID:The natural anti-Gal antibody, the B-like antigen, and human red cell aging. 246 Jan 63

Hemoglobin Malay (alpha 2 beta 2 19 Asn----Ser) has been observed in a few Malaysian patients with thalassemia intermedia. The beta Malay substitution increases the homology of the cryptic splice site at codons 17/18/19 of the beta-globin gene to the donor consensus splice sequence, suggesting that the beta-thalassemia associated with this mutation may be due to the generation of a new splice site. To test this hypothesis, we constructed a hybrid gene where we replaced part of a normal beta-globin gene with a PCR amplified region of the beta Malay gene. The expression of this mutant gene was studied in a heterologous transient expression system. The data show that nearly 25% of globin mRNA produced by this gene is abnormally spliced at the new splice site, providing a molecular mechanism for the beta-thalassemia associated with the mutation.
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PMID:Abnormal processing of beta-Malay globin RNA. 277 94

The Corfu delta beta zero thalassemia is characterized by the clinical picture of thalassemia intermedia. In the homozygous state there is a complete absence of hemoglobin (Hb) A and Hb A2 and a high level of Hb F. A DNA fragment containing the gamma and beta globin genes has been cosmid cloned, and the deletion breakpoint region, the beta globin gene and the promoter regions of the gamma globin genes sequenced. The deletion removes 7,201 base pairs (bp) containing part of the delta globin gene and sequences upstream. The beta globin gene contains a G----A mutation at IVS 1 position 5. The gamma globin gene promoters are normal. Analysis of the transcription of the mutated beta globin gene in transfected HeLa cells shows that normal message is produced at a level of approximately 20% compared with a normal gene, the remaining 80% being spliced at cryptic sites in exon 1 and intron 1. This indicates that the mutation in the beta globin gene is not the sole cause of the absence of Hb A in Corfu delta beta zero thalassemia. It is concluded that the 7.2 kilobase (kb) of deleted DNA contains sequences necessary for the normal activation of the beta globin gene. Possible mechanisms for the effect of the deletion on the expression of beta and gamma globin genes are discussed.
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PMID:The Corfu delta beta zero thalassemia: a small deletion acts at a distance to selectively abolish beta globin gene expression. 282 15

Studies on the effects of thalassemic mutations on gene function in vivo have clinical as well as scientific implications. Usually these studies have been performed on nucleated red blood cell (RBC) precursors normally present in bone marrow. Many patients with beta-thalassemia are splenectomized and may have high levels of nucleated RBC, orthochromatic normoblasts, in their peripheral blood (1-5% of total RBC). The possibility of exploiting these cells instead of bone marrow as a source for nuclear and cytoplasmic RNA for expression studies was investigated. A simple procedure was developed for enrichment for normoblasts in blood samples withdrawn from patients prior to transfusion. Globin transcripts were analyzed in RNA purified from 12 patients. Unspliced precursor beta-mRNA molecules were observed in a patient with beta o-thalassemia, homozygous for a mutation at the 5' IVS2 splice site of the beta-globin gene. Detailed analyses showed that his mature beta-mRNA was larger than normal, and that a cryptic 5' splice site, approximately 50 nucleotides downstream from the normal one, was utilized. We conclude that peripheral blood can be used as a reliable source of RNA for the analysis of the effects of beta-thalassemia mutations on gene expression and the relationship to the clinical condition. Moreover, this procedure facilitates the comparison of in vivo gene expression with the results obtained from DNA transfection experiments with cloned beta-thalassemia genes.
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PMID:Beta-thalassemia: analysis of mRNA precursors of a mutant human globin gene with defective splicing using peripheral blood nucleated red blood cells. 288 6


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