UMLS:C0039730 - FACTA Search

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 analysis of a number of cases of beta-globin thalassemia and hereditary persistence of fetal hemoglobin (HPFH) due to large deletions in the beta-globin locus has led to the identification of several DNA elements that have been implicated in the switch from human fetal gamma- to adult beta-globin gene expression. We have tested this hypothesis for an element that covers the minimal distance between the thalassemia and HPFH deletions and is thought to be responsible for the difference between a deletion HPFH and deltabeta-thalassemia, located 5' of the delta-globin gene. This element has been deleted from a yeast artificial chromosome (YAC) containing the complete human beta-globin locus. Analysis of this modified YAC in transgenic mice shows that early embryonic expression is unaffected, but in the fetal liver it is subject to position effects. In addition, the efficiency of transcription of the beta-globin gene is decreased, but the developmental silencing of the gamma-globin genes is unaffected by the deletion. These results show that the deleted element is involved in the activation of the beta-globin gene perhaps through the loss of a structural function required for gene activation by long-range interactions.
...
PMID:Deletion of a region that is a candidate for the difference between the deletion forms of hereditary persistence of fetal hemoglobin and deltabeta-thalassemia affects beta- but not gamma-globin gene expression. 1002 37

Hereditary persistence of fetal hemoglobin (HPFH) is a group of genetically heterogeneous conditions characterized by the continued expression of fetal hemoglobin in adulthood. These constitute natural models for understanding the mechanism(s) of the hemoglobin switch. Many large deletions in the beta-globin gene cluster and point mutations in one of the fetal globin gene promoters have been described before. In this study we describe a novel C-->A transversion (-114) in the distal CCAAT box of the Ggamma-globin gene promoter associated with the Ggammabeta+-HPFH phenotype in an Algerian family. Individuals heterozygous for this mutation exhibit moderate raise in Hb F levels (0.6-3.5%). Much higher Hb F levels (3.8-11.2%) are observed when a beta(o)-thalassemia allele is present in trans to the hereditary persistence of fetal hemoglobin allele. This novel Algerian HPFH mutation further stresses the importance of the distal CCAAT box in the postnatal regulation of gamma-globin gene expression.
...
PMID:A novel C-->A transversion within the distal CCAAT motif of the Ggamma-globin gene in the Algerian Ggammabeta+-hereditary persistence of fetal hemoglobin. 1033 83

We studied a family in which two inherited defects of the non-alpha-globin cluster segregate: Greek hereditary persistence of fetal hemoglobin (HPFH) and beta-thalassemia. The compound heterozygote is a healthy man with 43% HbF, Ggamma/Agamma ratio (27:73) differing from that of 10 simple heterozygotes for the Greek HPFH (92:8), normal levels of total Hb (13.3 g/dl), and reduced HbA2 levels comparing with the levels of beta-thal heterozygotes for the same mutation. Molecular analysis of the beta-globin genotype revealed the presence of the IVSII-745 (C-->G) beta+ RNA splice mutation in trans with the -117 G-->A Greek HPFH. The beta+ mutation was linked to haplotype VII and the Greek HPFH was associated with haplotype Ia. The father of the compound heterozygote carries the Greek HPFH in trans with the -158 C-->T on the Ggamma promoter, which is linked with haplotype IV. He presented 13.5% HbF with a Ggamma/Agamma ratio 75:25. His daughter was a compound heterozygote for the IVSII-745 mutation in trans with the -158 C-->T, while her HbF levels were 3.7% with a Ggamma/Agamma ratio 31:69.
...
PMID:Fetal hemoglobin expression in the compound heterozygous state for -117 (G-->A) Agamma HPFH and IVSII-745 (C-->G) beta+ thalassemia: a case study. 1036 95

Human beta-globin disorders, such as sickle cell anemia and beta-thalassemia, are relatively common genetic diseases cause by mutations in the beta-globin gene. Increasing gamma-globin gene expression has been found to greatly reduce the disease symptom. However, the gamma-globin gene is developmentally regulated and normally expressed at high levels only during the fetal stage of human development. We have explored the possibility of activating the gamma-globin gene expression by triplex-forming oligonucleotide (TFO)-directed targeted mutagenesis. Using a psoralen-conjugated TFO designed to bind to a site overlapping with an Oct-1 binding site at the -280 region of the gamma-globin gene, targeted mutagenesis of the Oct-1 binding site has been achieved by transfecting the in-vitro-formed plasmid-oligo complex into human normal fibroblast (NF) cells. The mutation frequency at the target site was estimated to be 20% by direct DNA sequencing analysis. In-vitro protein binding assays indicated that these mutations reduced Oct-1 binding to the target site. In-vivo gene expression assays demonstrated activation of gamma-globin gene expression from these mutations in mouse erythroleukemia (MEL) cells. The levels of the gamma-globin gene expression increased by as much as fourfold in mutants with single base changes. These results suggest that the -280 region of the Agamma-globin gene negatively regulates the gamma-globin gene expression, and mutations at the Oct-1 binding site can lead to activation of the gamma-globin gene and generate the hereditary persistence of fetal hemoglobin (HPFH) condition. This study may provide a novel approach for gene therapy of sickle cell disease. The data may also have implications in gene therapy for other diseases including genetic diseases and cancers by introducing mutations into transcription factor binding sites to alter the levels of target gene expression.
...
PMID:Activation of human gamma-globin gene expression via triplex-forming oligonucleotide (TFO)-directed mutations in the gamma-globin gene 5' flanking region. 1072 15

The splicing defect at IVS-I-110 is by far (43.15%) the most common beta-thalassaemia mutation in Greece. The - 117 (G-->A) Agamma hereditary persistence of fetal hemoglobin (Greek HPFH) is also the most frequent nondeletional HPFH in Greece. We report a case in which these two defects co-segregates. She is a healthy female where the total Hb is 12.3 g/dl with 51% HbF and normal HbA2. Her Ggamma/Agamma ratio is 35:65 differing from that of 10 simple heterozygotes for the Greek HPFH who have ratio of 8:92. Molecular analysis of the beta-globin genotype revealed the presence of the IVS-I-110 beta+ mutation in trans to the -117 G-->A Greek HPFH. Both mutations are linked to Ia. Her father has Greek HPFH in trans to the -158 C-->T on the Ggamma promoter, which is linked with haplotype IIIalpha. He has 13% HbF with a Ggamma/Agamma ratio 32:68. Her sister is a compound heterozygote for the IVS-I-110 mutation in trans to the - 158 C-->T, with HbF levels of 3% and a Ggamma/Agamma ratio 72:28.
...
PMID:Fetal hemoglobin expression in the compound heterozygous state for -117 (G-->A) Agamma HPFH and IVS-1 nt 110 (G-->A) beta+ thalassemia: a case study. 1096 67

Genetic factors affecting postnatal gamma-globin expression--a major modifier of the severity of both beta-thalassemia and sickle cell anemia--have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human gamma-globin. To model the human beta-cluster in mice, with the goal of screening for loci affecting human gamma-globin expression in vivo, we introduced a human beta-globin cluster YAC transgene into the genome of FVB/N mice. The beta-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) gamma allele, resulting in postnatal expression of human gamma-globin in transgenic mice. The level of human gamma-globin for various F1 hybrids derived from crosses between the FVB/N transgenics and other inbred mouse strains was assessed. The gamma-globin level of the (C3HeB/FeJ x FVB/N)F1 transgenic mice was noted to be significantly elevated. To map genes affecting postnatal y-globin expression, we performed a 20-centiMorgan (cM) genome scan of a (C3HeB/FeJ x FVB/N)F1 transgenics x FVB/N backcross, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within an 18-cM interval of mouse Chromosome (Chr) 1 (LOD = 4.3) that contributes 10.9% of variation in gamma-globin level. Combining transgenic modeling of the human beta-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human gamma-globin level in vivo.
...
PMID:Genome scan identifies a locus affecting gamma-globin level in human beta-cluster YAC transgenic mice. 1106 60

Hereditary persistence of fetal hemoglobin (HPFH) is one of the hemoglobinopathies in which the fetal gamma-globin genes remain active in adult life. Most HPFHs are caused by a large deletion involving a variable extent of DNA segment on the beta-globin gene cluster. We report the molecular defects associated with a deletional HPFH, which has previously been described in Cambodians and Vietnamese, in two unrelated Chinese individuals. To define the sequence around the breakpoints of the deletion, both the deletion junction fragment and the normal DNA across the breakpoints were cloned by PCR and sequenced. We found that the 5' breakpoint is located between nucleotides 986 and 987 upstream from the startpoint of the beta-globin gene, which further confirmed the Southeast Asian (SEA) HPFH deletion previously determined, whereas the 3' breakpoint, which is clarified for the first time by us, lies approximately 2.3 kb downstream from the 3' HS1 site of the beta-globin gene. It is suggested that deletions were the result of a non-homologous recombination event. Based on our novel sequence data, we designed a PCR amplification method with three primers bridging the 3' breakpoint. With this method and reverse dot blot (RDB) for detecting beta-thalassemia mutations, a Chinese family that had a 6-year-old propositus with severe thalassemia intermediate and that had requested prenatal diagnosis for the second pregnancy was found to be compound heterozygotes of HPFH defects with beta-thalassemia. The fetal genomic DNA diagnosis showed the same results as those in propositus, i.e., both of them inherited the deletion from their mother and inherited a codons 14-15 (+G) frameshift mutation causing beta-thalassemia from their father.
...
PMID:Molecular characterization and PCR detection of a deletional HPFH: application to rapid prenatal diagnosis for compound heterozygotes of this defect with beta-thalassemia in a Chinese family. 1107 32

We have studied a four-generation (23 subjects) African-American family with beta(o) thalassemia and high fetal hemoglobin (HbF) levels. The beta(o) thalassemia in this family is due to the splicing site mutation, beta IVS2+1G-->A, that leads to aberrant mRNA processing and the absence of beta globin. Two members of this family are homozygous for beta(o) thalassemia and are non-anemic. All family members who are heterozygous for the beta IVS2+1G-->A mutation have elevated HbF, with the exception of two individuals who also have severe alpha-globin chain deficiency. We excluded linkage with the hereditary persistence of fetal hemoglobin loci on chromosomes 6 and X. We also excluded the presence of all previously described determinants in the beta globin gene cluster associated with elevated HbF production. One thalassemia allele is in the Cameroon-like (HS2)/Benin-like beta globin gene cluster haplotype, and the other is in the Senegal-like (HS2)/Benin-like beta globin gene cluster haplotype. We speculate that in the homozygotes, those erythroid cells that express low to absent levels of gamma globin are selectively destroyed. In contrast, in the heterozygotes, the presence of the normal beta globin allele would ameliorate the globin chain imbalance and thus allow survival of erythroid cells that express the abnormal transcript, leading to a typical beta(o) thalassemia phenotype. Thus, the heterocellular gamma globin expression together with in vivo preferential survival of HbF-containing erythroid cells ameliorates Cooley's anemia in the beta(o) thalassemia homozygotes. It remains to be determined what sequences linked to each thalassemia allele and what trans-acting factors contribute to high HbF levels.
...
PMID:Non-anemic homozygous beta(o) thalassemia in an African-American family: association of high fetal hemoglobin levels with beta thalassemia alleles. 1155 36

The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I-110 G-->A, Cd 39 C-->T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.7+/-1.7%) and, interestingly, to depend on the type of the respective beta-thalassemia mutation, in trans to the nd-HPFH allele. All cases presented a typical beta-thalassemia heterozygote's phenotype despite the increased HbF and the normal HbA2 levels, as indicated by both the hematological indices and the biosynthetic ratios. These data were compared with those from two unique cases of Greek origin: a homozygous case of the Greek nd-HPFH and a compound heterozygote with HbS. Our data suggest that in these compound heterozygous cases the beta-thalassemic chromosome indirectly determines the final outcome of the gamma- and of the in cis beta-globin gene expression, most likely at the post-transcriptional level.
...
PMID:A comparative study of Greek nondeletional hereditary persistence of fetal hemoglobin and beta-thalassemia compound heterozygotes. 1197 33

The cellular distribution of hemoglobin F is important for evaluating persistently elevated hemoglobin F levels, such as in hereditary persistence of fetal hemoglobin (HPFH) or delta/beta-thalassemia, and for differentiating homozygous hemoglobin S (or hemoglobin S-beta(0)-thalassemia) from hemoglobin S-HPFH, traditionally done by using the Kleihauer-Betke (K-B) acid elution test. We evaluated a flow cytometric method using an anti-hemoglobin F antibody as a replacement for the K-B test. We used 172 specimens representing a variety of conditions: HPFH trait, 19 cases; delta/beta-thalassemia trait, 8 cases; hemoglobin S-HPFH, 10 cases. By flow cytometry, all cases of HPFH trait gave a hemoglobin F pattern comparable to the homocellular pattern obtained by the K-B test; all cases of delta/beta-thalassemia tested gave a pattern comparable to a K-B heterocellular pattern. Most cases of hemoglobin S-HPFH gave a homocellular distribution of hemoglobin F whereas all cases of homozygous hemoglobin S with elevated hemoglobin F levels gave a heterocellular pattern. Flow cytometry provides a more rapid and objective method for assessing cellular distribution of hemoglobin F and is useful for patient evaluation when HPFH trait, delta/beta-thalassemia trait, or hemoglobin S-HPFH trait is suspected.
...
PMID:Flow cytometric measurement of hemoglobin F in RBCs: diagnostic usefulness in the distinction of hereditary persistence of fetal hemoglobin (HPFH) and hemoglobin S-hPFH from other conditions with elevated levels of hemoglobin F. 1204 36

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>