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

The present review provides a summary of quantitative hemoglobin data and lists the results of gene mapping and sequencing analyses for blood samples from newborn babies of different countries. Methodology suitable for such studies is reviewed, various abnormal fetal hemoglobins are discussed, the occurrence of Hb Bart's (gamma 4) and of the embryonic zeta chain is evaluated, and the various types of gamma-globin gene rearrangements (-A gamma.A gamma-; -G gamma.G gamma-; gamma-thalassemia; gamma-globin gene triplications, quadruplications, and quintuplications) are compared. The several tables list the frequencies of the common A gamma T variant and of the different gamma gene rearrangements in various populations, while the results of quantitative analyses suggest that most anomalies are not associated with disease.
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PMID:Gamma chain abnormalities and gamma-globin gene rearrangements in newborn babies of various populations. 180 81

We have developed a technique to diagnose the alpha- and beta-thalassemia (thal) syndromes using the polymerase chain reaction to amplify cDNA copies of circulating erythroid cell messenger RNA (mRNA) so as to quantitate the relative amounts of alpha-, beta-, and gamma-globin mRNA contained therein. Quantitation, performed by scintillation counting of 32P-dCTP incorporated into specific globin cDNA bands, showed ratios of alpha/beta-globin mRNA greater than 10-fold and greater than fivefold increased in patients with beta 0- and beta (+)-thal, respectively, as well as a relative increase in gamma-globin mRNA levels. Conversely, patients with alpha-thalassemia showed a decreased ratio of alpha/beta-globin mRNA proportional to the number of alpha-globin genes deleted. This methodology of ascertaining ratios of globin mRNA species provides a new, simplified approach toward the diagnosis of thalassemia syndromes, and may be of value in other studies of globin gene expression at the transcription level.
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PMID:Diagnosis of thalassemia using cDNA amplification of circulating erythroid cell mRNA with the polymerase chain reaction. 162 91

Although some cases of the syndrome of hereditary persistence of fetal hemoglobin (HPFH) have been correlated with mutations causing a change in the binding of trans-acting factors to DNA sequences flanking the gamma-globin gene, this mechanism has not been described in beta-thalassemias upstream of the canonical promoter of the beta-globin gene. In this report we describe such a change in binding of a protein that may explain a silent carrier phenotype of beta-thalassemia. We have previously demonstrated the binding of a protein (BP1) derived from a nuclear extract of human K562 cells to DNA 5' to the human beta-globin gene in a region having a negative regulatory function. The binding of BP1 in this region can be detected by DNAse I footprinting and by gel mobility shift analysis. We have now compared binding of BP1 to the normal sequence and a mutated sequence (+ATA/-T at -530 bp from the cap site) from the silent carrier of beta-thalassemia. Using mobility shift assays we show that BP1 binds about nine times more strongly to the mutated sequence than the normal sequence. These results suggest the possibility that the decreased expression of the beta-globin gene exhibited by the carrier may be due, at least in part, to tighter binding of a protein which functions as a negative control element or repressor.
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PMID:Increased protein binding to a -530 mutation of the human beta-globin gene associated with decreased beta-globin synthesis. 198 81

We have identified a novel repetitive family in human DNA. One member of this family is found downstream of the beta-globin gene cluster between the 3' breakpoints of the deletions associated with Chinese G gamma + (A gamma delta beta)O thalassemia and HPFH-2. This repetitive element is approximately 6 kbp in length and includes terminal direct repeats of 415 bp. Numerous DNA sequence features of the direct repeats (LTRs) and their flanking regions indicate that the element is a retrovirus-like structure. The most striking of these features is the presence of a histidine tRNA binding site just 3' to the 5' LTR. Accordingly the element is named RTVL-H (retrovirus-like element-histidine). The LTRs of the RTVL-H element are not strongly homologous to the LTRs of any previously described mammalian retrovirus or retrovirus-like element. Copy number estimates suggest that there are approximately 1000 RTVL-H elements in the human genome. The element found 3' (greater than 60 kbp) to the beta-globin gene appears to be a stable part of the normal genome. This retrovirus-like element is brought close to the fetal gamma-globin locus by the Chinese thalassemia deletion but is deleted in HPFH-1 and HPFH-2.
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PMID:A retrovirus-like element occurs between the 3' breakpoints of two large deletions in the human beta-globin gene cluster. 241 85

Data were obtained on blood samples from a relatively large group (264) of healthy Japanese newborns, collected at hospitals in Tokyo, Kurashiki, and Ube. The studies included an evaluation of anomalies in alpha-globin gene and gamma-globin gene arrangements using gene mapping and gamma-chain composition analyses. The results confirmed the rarity of alpha-thalassemia among Japanese; only a few babies had alpha-thalassemia-2 trait (the -3.7-kilobase [kb] deletion), while others had alpha-globin gene triplications (both the alpha alpha alpha anti-3.7 and the alpha alpha alpha anti-4.2 types). Among the gamma-globin gene anomalies that were observed, a few babies had the -A gamma-A gamma- globin gene arrangement or the -G gamma A gamma- type of deletion. The gamma-chain triplication (-G gamma-A gamma G gamma-A gamma-) occurred in 10 out of 256 newborns, and its frequency exceeded that of its corresponding -G gamma A gamma- deletion by a factor of 5. The restriction endonuclease XmnI was a useful tool, in addition to the enzymes Bg1II and BclI, to evaluate and confirm the gamma-globin gene deletion and triplication. The A gamma T variant, which is the product of a mutant A gamma-globin gene, occurred at a frequency of 0.156. The chromosome carrying this mutant A gamma gene had a characteristic haplotype that was originally seen in black and Mediterranean patients with Hemoglobin (Hb) S or with beta-thalassemia.
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PMID:Abnormal arrangements in the alpha- and gamma-globin gene clusters in a relatively large group of Japanese newborns. 241 79

We have studied the hematology, hemoglobin composition, and globin gene arrangements in one young Turkish boy with a beta zero-thalassemia homozygosity and in 11 of his relatives. Evidence is presented that the chromosome with the beta zero-thalassemia determinant carries a gamma-globin gene quadruplication, perhaps in a -G gamma-G gamma-G gamma-A gamma-gene arrangement. The eight gamma-globin genes in this patient produced G gamma and A gamma chains in a 95 to 5 ratio, and nearly 99% of the patient's hemoglobin was of the fetal type. The clinical condition resembled that of a thalassemia intermedia. HbF levels in eight beta-thalassemia heterozygotes varied between 0.5 and 4.2% and the percentages of G gamma in this HbF averaged at 87% or 95%; this level is to some extent related to the haplotype of the normal chromosome. All subjects carried four alpha-globin genes; a new BglII polymorphism was observed within the psi alpha-globin gene.
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PMID:Beta zero-thalassemia in association with a gamma-globin gene quadruplication. 243 Jun 48

This paper summarizes various anomalies involving the duplicated gamma-globin genes which are normally arranged as -G gamma-A gamma-. Variations include G gamma----A gamma and A gamma----G gamma replacements; newborn heterozygotes for these anomalies have low G gamma (A gamma A gamma/G gamma A gamma) or high G gamma values (G gamma G gamma/G gamma A gamma). Additional abnormalities include the deletion of one gamma-globin gene (-A gamma-; gamma-thalassemia), gamma-globin gene triplications (G gamma-AG gamma-A gamma; G gamma-G gamma-A gamma) and gamma-globin gene quadruplications (G gamma-G gamma-G gamma-A gamma-); several of these conditions are found in different populations but at low frequencies. In adults, the G gamma to A gamma ratio in the Hb F and often also the Hb F level, are directly related to specific structural characteristics of the chromosome; specific mutations in the promoter sequences 5' to G gamma or to A gamma, for instance, may result in increased G gamma or A gamma chain production with an increase in Hb F levels (nondeletional G gamma- or A gamma-HPFH) or with only modest changes in the total Hb F (normal adults; Swiss-HPFH). Similar variations have been observed in SS patients.
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PMID:A short review of human gamma-globin gene anomalies. 244 59

A survey of hemoglobinopathies in northern Sardinia revealed a high frequency (0.3%) of carriers of a hematologic condition characterized by increased expression of fetal hemoglobin during adult life (hereditary persistence of fetal hemoglobin or HPFH). In spite of a normal hematologic phenotype, the heterozygous carriers for this condition display about 12% HbF, almost exclusively of the A gamma type; compound heterozygotes with beta-thalassemia have 20%-26% HbF and run a very mild clinical course. The sequence analysis of the cloned A gamma gene linked to the HPFH determinant revealed the presence of a G----A substitution at position -117 of the A gamma-globin gene promoter; the same mutation occurs also in Greek HPFH, although associated with different restriction polymorphisms. Another hereditary condition characterized by increased HbF (alpha 2 A gamma 2) level and a mild thalassemia phenotype in Sardinia is associated with the -196C----T substitution in the A gamma-globin gene promoter (Sardinian delta beta-thalassemia). Population studies using oligonucleotides complementary both to the -117 G----A and -196C----T mutations and the corresponding normal sequences confirm the presence of these mutations only in HPFH and delta beta-thalassemia chromosomes and exclude these changes being common DNA polymorphisms.
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PMID:A frequent A gamma-hereditary persistence of fetal hemoglobin in northern Sardinia: its molecular basis and hematologic phenotype in heterozygotes and compound heterozygotes with beta-thalassemia. 245 84

We have molecularly characterized a novel (A gamma delta beta)zero-thalassemia associated with increased synthesis of HbF in three members of a German family. The levels of HbF in the peripheral blood red cells of the heterozygotes ranged between 9.9% and 12.5% with a heterocellular distribution in the red cells, as detected by immunofluorescence. The mutation resulted from a deletion starting about 1.5 to 1.9 kb from the 3' end of the G gamma-gene and ending 27 +/- 0.5 kb 3' to the beta-globin gene. Thus, the total deletion is 52 +/- 0.5 kb. Its 5' breakpoint is similar to that of the previously described (A gamma delta beta)zero-thalassemias, while the location of the 3' breakpoint is placed very close to the 3' breakpoints of HPFH-4 and HPFH-3 deletions. The proximity of the 3' breakpoint of the German (A gamma delta beta)zero-thalassemia to those of HPFH-3 and HPFH-4 deletions raises the possibility that a common mechanism, such as the juxtaposition of an enhancer, might underlie the activation of the gamma-globin genes in these three mutants.
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PMID:Molecular characterization of a novel form of (A gamma delta beta)zero-thalassemia deletion with a 3' breakpoint close to those of HPFH-3 and HPFH-4: insights for a common regulatory mechanism. 245 21

We have identified and molecularly characterized a novel deletion in the beta-globin gene cluster that increases fetal hemoglobin (HbF) synthesis in a 24-year-old Laotian man who is heterozygous for this mutation. The patient is asymptomatic with a mild anemia, hypochromia, and microcytosis (Ht = 39%, MCH = 22.8 pg, MCV = 71 fl), normal levels of HbA2 (3.0%) and 11.5% HbF (G gamma A gamma ratio 60 to 40), with heterocellular distribution (52% F cells). Extensive restriction endonuclease mapping defined the 5' breakpoint within the IVS II of the delta-globin gene, between positions 775 to 781 very similar to the 5' breakpoint of the Sicilian delta beta-thalassemia. However, the 3' breakpoint was localized between two Pst I sites 4.7 kb 3' of the beta-globin gene, thus ending about 0.7 kb upstream from the 3' breakpoint of the Sicilian delta beta-thalassemia. This results in a 12.5 kb deletion of DNA. It is of interest that the 5' breakpoint of the deletion residues within an AT-rich region which has been proposed as a specific recognition signal for recombination events, while the 3' breakpoint lies within a cluster of L1 repetitive sequences (formerly known as Kpn I family repeats). The presence of the 3' breakpoints of several other deletions within this region of L1 repeats also suggests that such sequences might serve as hot spots for recombination and eventually lead to thalassemia deletions. The similarity of the 5' and 3' breakpoints of these delta beta-thalassemias underscores the putative regulatory role of the deleted and juxtaposed sequences on the expression of the gamma-globin genes in adult life.
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PMID:Laotian (delta beta) (0)-thalassemia: molecular characterization of a novel deletion associated with increased production of fetal hemoglobin. 245 54


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