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)

The intermediate character of beta-thalassaemia may be due to a molecular cause capable of reducing the unbalance between alpha and non-alpha chains. We report the case of a child born of consanguineous parents and homozygous for beta-thalassaemia. The patient was irregularly transfused until puberty. His haemoglobin level was around 10 g/dl, and in his erythroid line only foetal haemoglobin was synthesized, except for small amounts of haemoglobin A2. An in vitro study of globin chains biosynthesis confirmed the total absence of beta chains synthesis, and the molecular defect was characterized. This was deletion of a colon 6 nucleotide on both chromosomes, making the messenger RNA unstable and non-traducible. The initial diagnostic approach in this patient included the indirect determination of restriction polymorphism (Orkin's halotype IX), a search for the presence or absence of a nonsense codon 39 often associated with haplotype IX, and the demonstration of a frameshift in the reading phase of codon 6. The very high synthesis of foetal haemoglobin in this patient seems to be linked with a C----T substitution in -158 of the G gamma gene creating an Xmnl site and a gamma phi beta (+-++) subhaplotype which appears to be related in all haemoglobinopathies to an increased synthesis of foetal haemoglobin with predominant G gamma chain.
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PMID:[Intermediate homozygous beta-thalassemia with high fetal hemoglobin synthesis. Molecular analysis]. 246 87

In this study we have carried out alpha- and beta-globin gene analysis and defined the beta-globin gene polymorphisms in a group of patients with thalassemia intermedia of Sardinian descent. A group of patients (109) with thalassemia major of the same origin served as control. Characterization of the beta-thalassemia mutation showed either a frameshift mutation at codon 6 or a codon 39 nonsense mutation. We found that homozygotes for the frameshift mutation at codon 6 or compound heterozygotes for this mutation and for the codon 39 nonsense mutation develop thalassemia intermedia more frequently than thalassemia major. The frameshift mutation at codon 6 was associated with haplotype IX that contains the C-T change at position -158 5' to the G gamma globin gene implicated in high gamma chain production and thus the mild phenotype. In patients' homozygotes for codon 39 nonsense mutation, those with thalassemia intermedia more frequently had the two-gene deletion form of alpha-thalassemia, or functional loss of the alpha 2 gene as compared with those with thalassemia major. In a few siblings with thalassemia major and intermedia, the thalassemia intermedia syndrome correlated with the presence of the -alpha/-alpha genotype. No cause for the mild phenotype was detected in the majority of patients who had not inherited either haplotype IX or alpha-thalassemia.
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PMID:Molecular analysis of beta zero-thalassemia intermedia in Sardinia. 247 6

This study shows a marked and protracted activation of HbF synthesis in homozygous beta.-thalassaemia patients transplanted from HLA identical siblings heterozygous for beta-thalassaemia, as compared to patients transplanted from normal donors. HbF synthesis in recipients was much higher in relation to the corresponding bone marrow donor values either normal or heterozygous for beta thalassaemia. gamma-chain synthesis and G gamma/A gamma ratio were also studied in peripheral blood BFU-E from recipients and their donors. BFU-E from donors heterozygous for beta-thalassaemia showed higher gamma chain synthesis as compared to normal donors. Peripheral blood BFU-E gamma/beta + gamma ratios and G gamma percentage were higher in recipients than in their corresponding donors both normal or heterozygotes. The marked and protracted reactivation of HbF synthesis in recipients of heterozygous beta-thalassaemia bone marrow most likely results from an increased erythropoietic stress on erythroid progenitors. In order to obtain adequate Hb levels heterozygous beta-thalassaemia bone marrow should produce more red blood cells to compensate for the low MCH. The magnitude of activation of HbF synthesis was very variable. This variability may result from inherited differences in the capacity of reactivation of HbF synthesis of red cell progenitors from heterozygous beta-thalassaemia under stressed erythropoiesis.
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PMID:Erythropoiesis following bone marrow transplantation from donors heterozygous for beta-thalassaemia. 247 70

The gamma chain composition of HbF in 37 beta-thalassemia homozygotes and 85 unselected newborn babies from Brazil was studied by high performance liquid chromatography (HPLC). The G gamma value of 59.5 +/- 7.5% (mean +/- SD) obtained for the beta-thalassemia homozygotes was significantly lower than the newborn value of 71.2 +/- 4.2%. The A gamma T gene frequency was 0.159 for the newborns and 0.454 for the thalassemia homozygotes. The A gamma T gene occurred both in chromosomes bearing the beta(0)-thalassemia gene and those with the beta(+)-thalassemia gene.
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PMID:Fetal hemoglobin heterogeneity in Brazilian newborns and beta-thalassemia homozygotes. 247 18

The occurrence of gamma-chain abnormal hemoglobins and of gamma-thalassemia in Chinese newborns was evaluated through analyses of the Hb F of over 1,100 babies and of the DNA from one baby and his parents. Gene mapping data identified this baby as a homozygote for -G gamma A gamma-thalassemia, which is caused by a deletion of about 5 kb due to an unequal crossing-over between the -G gamma- and -A gamma- genes. This condition is the same as that observed in Indian and Japanese babies [2,3]. Its gene frequency among babies from the Shanghai area was 0.012. A previously unrecognized G gamma chain variant, Hb F-Shanghai or alpha 2 G gamma 266(E10)Lys----Arg, was observed in one newborn. This variant was not detected by conventional techniques but only by high performance liquid chromatography, as the G gamma 66 Lys and G gamma 66 Arg chains had slightly different chromatographic mobilities. Lys at position gamma 66 participates in contacts with the heme group, and its substitution by another amino acid residue might interfere with physiochemical and/or functional properties. No other gamma-chain variants have been detected except the well-known A gamma T or F-Sardinia chain (f.A gamma T = 0.076).
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PMID:-G gamma A gamma-Thalassemia and gamma-chain variants in Chinese newborn babies. 257 47

Fetal haemoglobin (alpha 2 gamma 2) is predominant in red cells of the fetus and newborn baby, and is largely replaced after birth by adult haemoglobin (alpha 2 beta 2). The two types of gamma chains (A gamma and G gamma) are generally less than 1% of total beta-like chain in adults, and the G gamma: A gamma ratio is typically 40:60. Higher G gamma values (greater than 50% of gamma chain) are frequently associated with a T for C nucleotide substitution 158 base pairs 5' of the G gamma Cap site (-158). The first exception to this rule was a beta o-thalassaemia in a Black family that was associated with about 60% G gamma in heterozygotes. A DNA fragment containing the G gamma and A gamma genes of the high G gamma haplotype of this case has now been cloned. DNA sequencing from -383 to the Cap site showed no differences from normal for the G gamma gene, except for C at -158. For the A gamma gene, however, a deletion of four base pairs (AGCA) at -222 to -225 was found. It is hypothesized that this deletion causes reduced A gamma globin gene expression in adults, which suggests that promoter elements important for the regulation of fetal haemoglobin expression in adults extend upstream at least to -225.
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PMID:Four base-pair DNA deletion in human A gamma globin-gene promoter associated with low A gamma expression in adults. 337 86

Members of a Black family from Georgia who were investigated for the first time in 1960 and several times thereafter were reinvestigated through DNA restriction endonuclease analyses and haplotyping, while the gamma chain heterogeneity of the Hb F was reevaluated using a newly developed HPLC procedure. Four different abnormalities were present. (a) Heterozygosity for G gamma A gamma-HPFH type II characterized by a large deletion involving the delta and beta globin genes with a 5' end within the psi beta gene. (b) Heterozygosity for an -epsilon-G gamma-G gamma-psi beta-delta-beta S-chromosome, thus carrying a beta S globin gene and two G gamma genes instead of one G gamma and one A gamma gene. (c) Heterozygosity for an -epsilon-G gamma-A gamma T-psi beta-delta-beta S-chromosome, carrying the beta S globin gene and an allele of the A gamma (or A gamma I) gene. These three chromosomes occurred in combination with each other, resulting in SS and S-HPFH conditions, and with a normal -epsilon-G gamma-A gamma-psi beta-delta-beta A-chromosome resulting in the HPFH and Hb S heterozygosities. The presence of the -G gamma-G gamma- and -G gamma-A gamma T-chromosomes in the one SS patient was responsible for the high G gamma value (average 75%), 25% A gamma T chain, and for the absence of the A gamma I chain. (d) An alpha-thalassemia-2 heterozygosity in one member.
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PMID:Hemoglobin abnormalities in a black family with HB S, hereditary persistence of HB F, and a gamma chain variant; a reevaluation through gene mapping. 608 52

The synthesis of alpha and non-alpha chains (beta, delta, G gamma, and A gamma) was studied in cultures of peripheral blood mononuclear cells from eleven beta-thalassemia heterozygotes, two HPFH heterozygotes, and one HPFH homozygote. The synthesis of Hb F in the thalassemia colonies (average value: 12.6%) was comparable to that in normal adult colonies (average value: 12.6%) was comparable to that in normal adult colonies (average value: 12.2%). The percent G gamma chain in the Hb F varied greatly but a relationship between the G gamma chain percentage in the Hb F from colonies and that from peripheral blood was established. The relative synthesis of Hb A2 in colonies of beta-thalassemia heterozygotes (average value: 5.8%) was 1.6 times as much as that in colonies of normal adults (average value: 3.6%). Hb A2 and Hb A were absent in the colonies of the HPFH homozygote. The alpha/non-alpha (i.e., beta, gamma, and delta) ratio of the hemoglobins in the cultured cells of the beta-thalassemia heterozygotes and the alpha/beta and alpha/beta ratios of isolated Hb A and Hb A2 were about one (range 0.74 to 1.38). The alpha/gamma ratio of the Hb F synthesized in BFUe-derived colonies of the HPFH homozygote, however, was 1.5. These results suggest a deficiency in the in vitro culture system resulting in decreased levels of alpha-mRNA or in a partial inhibition of initiation of protein synthesis which is known to reduce the synthesis of alpha chains more than that of the beta chains.
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PMID:Adult and fetal hemoglobin production in erythroid colonies from subjects with beta-thalassemia or with hereditary persistance of fetal hemoglobin (HPFH). 615 1

Fetal haemoglobin (Hb F) synthesis has been studied in 22 cases of sickle cell anemia (SS) from Saudi Arabia and compared with an equal number of cases of African origin. Among the Saudi Arabs gamma chain synthesis ranged from 4.0% to 19.9% of the total non-alpha chain synthesis (mean 8.1%) while the corresponding range for the Negro cases was < 0.3% to 4.6% (mean 1.7%). In both groups the peripheral blood Hb F level was on average 3--4 times higher than the proportion synthesized, indicating that the selective survival of Hb F containing cells (F cells) was an important factor in determining the final Hb F levels. Among the Saudi Arab cases there was a significant negative correlation between the degree of F cell enrichment and either the Hb F level of the percentage gamma chain synthesis. No such correlation was observed among the Negro cases. A high proportion of the cases in both groups were carriers of alpha thalassaemia in addition to SS, but no effect of alpha thalassaemia on Hb F production was observed.
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PMID:Hb F synthesis in sickle cell anaemia: a comparison of Saudi Arab cases with those of African origin. 615 84

Individuals heterozygous for the Greek (A gamma) variant of hereditary persistence of fetal haemoglobin (HPFH) synthesize Hb F whose gamma-globin chains are predominantly of the A gamma type. DNA obtained from Greek HPFH heterozygotes was used to test for abnormalities in the organization of non alpha-globin genes. In addition, gamma- and beta-globin expression was studied in BFUe cultures. Restriction endonuclease mapping showed that the G gamma, delta and beta genes in cis to the Greek HPFH determinant are intact. Overproduction of gamma-globin chains synthesis was observed in the BFUe cultures. A significant portion of the gamma chain synthesis was of the G gamma type, suggesting that the G gamma genes cis and trans to the HPFH chromosome are active in culture. DNA mapping data indicate that in contrast to G gamma A gamma HPFH and the G gamma (delta beta) thalassaemia, the Greek (A gamma) HPFH is not due to a large deletion in the non-alpha globin gene region. It is possible that the anomaly may result either from a small deletion or point mutation which influences non alpha-globin transcription. The in vitro synthesis data suggest that the low level of G gamma-globin chain synthesis in vivo is not the result of transcriptional inactivation of the G gamma gene, since this gene appears to be expressed in erythroid cell cultures. We speculate that the genetic lesion in Greek (A gamma) HPFH is in regulatory sequences which control the level of G gamma and A gamma expression during development.
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PMID:Greek (A gamma) variant of hereditary persistence of fetal haemoglobin: globin gene organization and studies of expression of fetal haemoglobins in clonal erythroid cultures. 617 32


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