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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

A recently developed high performance liquid chromatographic (HPLC) procedure using a weak cation exchanger (PolyCAT) in columns of different sizes was used to quantify fetal hemoglobin (HbF) in blood of normal adults and beta-thalassemia (beta-thal) heterozygotes with ten different types of mutations. Preparative PolyCAT-HPLC greatly facilitated the characterization of isolated HbF, i.e., the determination of the relative quantities of the G gamma and A gamma chains. The method is accurate and allows quantitation of Hb F at the 0.5% level; preparative PolyCAT-HPLC allows isolation of (nearly) pure Hb F from blood samples with low (less than 1%) Hb F. Adult Hb F levels were determined in 69 normal adults (including 24 diabetics); Hb F levels fell below 1% except for subjects with abnormal -- G gamma -- G gamma -- arrangement and a C----T mutation at position -158 relative to the Cap site of both G gamma genes. The effect of the same mutation in the normal -- G gamma -- A gamma-arrangement was variable. Certain beta-thal mutations (namely, those at positions -29; -88; IVS-I-1; IVS-II-1) were associated with high Hb F levels in heterozygotes, while those at nucleotide (nt) positions IVS-I-6; IVS-I-110; codon 24; codon 39; codons 41/42; IVS-II-745 were not. G gamma values varied and often fell into two groups (high G gamma and low G gamma); high G gamma values were not associated with high Hb F values. The chromatographic procedure is ideally suited for Hb A2 quantitation. Average values of Hb A2 in beta-thal heterozygotes with any one of nine of the ten mutations were twice that of normals; the one exception was the beta-thal heterozygote with the IVS-I-6 (T----C) mutation with an average low Hb A2 value of 3.6%.
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PMID:Fetal hemoglobin in normal adults and beta-thalassemia heterozygotes. 169 61

We have analyzed the levels and composition of the fetal hemoglobin (Hb F) in several members of a Czechoslovakian family with a heterozygosity for a newly discovered beta zero-thalassemia (codons 38/39; -C), or for a newly detected nondeletional hereditary persistence of fetal hemoglobin (a form of Swiss-HPFH with an A----C mutation at nucleotide -100 5' to the Cap site of G gamma), or with a compound heterozygosity for these two conditions. The Hb F level in the beta zero-thalassemia heterozygotes averaged approximately 0.3% with low G gamma values (approximately 28%) and relatively high A gamma T values (approximately 50%), that in the two Swiss-HPFH heterozygotes averaged 0.8% with approximately 95% G gamma, while that of the compound heterozygote was 3.1% with approximately 95% G gamma. The low Hb F levels were determined with a recently published cation exchange high-performance liquid chromatography (HPLC) procedure that is accurate at the 0.1%-0.2% Hb F level. This method, together with a reversed-phase HPLC procedure, made it possible to detect this unusual type of nondeletional G gamma-HPFH and provided the data indicating that the increased Hb F in the compound heterozygote was derived mainly from the chromosome with the HPFH determinant.
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PMID:Compound heterozygosity for a beta zero-thalassemia (frameshift codons 38/39; -C) and a nondeletional Swiss type of HPFH (A----C at NT -110, G gamma) in a Czechoslovakian family. 171 97

We describe the occurrence of a chromosome with a G----A mutation at position +22 relative to the Cap site that was found in five patients with beta-thalassemia. All patients had a common type of beta-thalassemia mutation on the second chromosome, namely the frameshift at codon 8 (-AA), the IVS-I-110 (G----A) and the IVS-II-1 (G----A) mutations. The beta genes of two patients, including the 5' and 3' untranslated regions, were completely sequenced and no other mutations, except a few polymorphic sites, were observed. Dot-blot analyses failed to demonstrate this G----A mutation at +22 in nearly 400 beta-thalassemia chromosomes and 180 normal chromosomes. Heterozygotes have the features of a high Hb A2-beta-thalassemia heterozygosity, although the hematological parameters might be less abnormal than observed in heterozygotes for the more common beta-thalassemia mutations. The possibility has been presented suggesting that this mutation might impair the binding of mRNA to ribosomes. Another mutation in this segment of DNA, i.e. a C----G mutation at position +20, is observed exclusively on a chromosome which also carries the C----G mutation at IVS-II-745. It is postulated that the +20 C----G mutation accentuates the beta-thalassemia condition caused by the IVS-II-745 mutation; the mechanism might be similar to that suggested for the G----A at +22 mutation.
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PMID:The G----A mutation at position +22 3' to the Cap site of the beta-globin gene as a possible cause for a beta-thalassemia. 171 6

Detailed gene mapping analyses of genomic DNA from two Turkish subjects with a beta-thalassemia trait demonstrated an approximately 300 bp deletion, which is located between the Rsa I restriction site 128 bp 5' to the Cap site and the Acc I restriction site 284 bp 3' to the same Cap site; it includes the 5' beta promoter region, the first exon, and (part of) the IVS-I. Heterozygotes for this and two other beta-thalassemia types, which are also caused by deletions involving 5' beta promoter sequences, appear to have higher hemoglobin (Hb) A2 levels, perhaps because the loss of this promoter results in an increased transcription of the delta globin gene, as delta and beta promoters may be influenced by the same enhancing sequences 3' to the beta globin gene.
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PMID:An approximately 300 bp deletion involving part of the 5' beta-globin gene region is observed in members of a Turkish family with beta-thalassemia. 244 May 2

The presence of various substitutions and deletions resulting in beta-thalassemia was studied in 19 black patients with homozygous beta-thalassemia and in numerous relatives; all patients were from Georgia, South Carolina, and Alabama. Methodology included gene mapping, amplification of genomic DNA with Taq polymerase, identification of known nucleotide substitutions or a single nucleotide deletion through hybridization with synthetic oligonucleotides, cloning and sequencing of a beta-globin gene, and sequencing of amplified genomic DNA. Of the 38 chromosomes tested, 21 (55%) had the A----G substitution at nt -29, eight (21%) had the C----T substitution at nt -88, three (8%) had the substitution at codon 24, while one each of the following abnormalities were also detected: frameshift at codon 6, a C----A mutation at nt 848 of the beta IVS-II (new), an A----T mutation at codon 61 (new), a deletion of 1.35 kilobases including the 5' end of beta, a Ggamma(Agamma delta beta)(0)-thalassemia, and one thalassemia determinant that remained unidentified. The C----A mutation at nt 848 of IVS-II occurred at a position 3 nucleotides 5' to the third exon, adjacent to the invariant AG dinucleotide of the acceptor sequence. The A----T mutation in codon 61 (AAG----TAG) resulted in the creation of a stop codon and thus in beta(0)-thalassemia. The various mutations occurred on chromosomes with different haplotypes; however, chromosomes with a specific mutation but with different haplotypes belonged to one specific framework, which suggested that crossovers were responsible for these different types. Hemoglobin (Hb) F levels were generally high (55% to 75% with 98.5% in one patient with beta(0)/beta(0)); a few patients with specific haplotypes and an alpha-thalassemia-2 heterozygosity had a lower Hb F level. The Ggamma in the Hb F was consistently high when the C----T mutation occurred at nt -158 to the Cap site of the Ggamma-globin gene; seven patients with +/+ at this site had an average Ggamma of 73.8%, eight patients with +/- had 64.8%, and one patient with -/- had 34.2%. Variations in hematologic values and in Hb F, Ggamma, and Hb A2 levels of relatives with a beta-thalassemia heterozygosity depended to some extent on the types of mutations or deletions and on the haplotypes of the chromosomes with the beta-thalassemia determinant.
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PMID:Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. 245 45

beta-thalassaemia is a haematological disorder which is rare in The Netherlands although the influx of carriers from Mediterranean, West Indian, and South American countries has increased its frequency. Only a few homozygotes have been found among the original Dutch population. In this article, we describe the molecular abnormality observed in two such homozygotes. Both patients were mildly affected and had the same C-G mutation in the beta-globin gene promoter at position -87 relative to the Cap site of the beta gene. This mutation is known to cause a mild beta +-thalassaemia. Additional studies of the epsilon-gamma-delta-beta-globin gene complex on chromosome II, i.e. haplotype analyses, identified three different haplotypes in the two patients. However, crossovers might have been responsible for these differences because the 3' haplotype, which involves restriction sites within and 3' to the beta-globin gene, was the same for all four chromosomes in the two homozygotes.
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PMID:[Homozygote beta-thalassemia in 2 Dutch families]. 247 96

Sequence analyses and dot-blot analyses with synthetic oligonucleotide probes have identified eight individuals in three Turkish families and one Bulgarian family with one chromosome having a C----T mutation at nucleotide position--101 relative to the Cap site of the beta-globin gene. This nucleotide is part of one of the conserved blocks of nucleotides within the promoter region; in vitro expression analyses with the chloramphenicol acetyltransferase system showed that this substitution will decrease the effectiveness of transcription. Five subjects had a thalassemia intermedia due to the additional presence of a known classical high hemoglobin (Hb) A2 beta-thalassemia mutation on the second chromosome; their hematologic condition was relatively mild. The three persons with a heterozygosity for the--101 C----T mutation had normal hematologic data without microcytosis but with high-normal levels of Hb A2 and a mild imbalance in chain synthesis. The newly discovered mutation is considered one of the silent types of beta-thalassemia. It is relatively rare because it was absent among several hundred normal and beta-thalassemia chromosomes.
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PMID:A C----T substitution at nt--101 in a conserved DNA sequence of the promotor region of the beta-globin gene is associated with "silent" beta-thalassemia. 271 3

We have examined the alpha globin gene complex for 49 individuals with alpha-thalassemia-2 (-alpha 3.7). Crossovers resulting in alpha-thalassemia-2 (type I) were observed in all 57 chromosomes with the -alpha 3.7 defect. Except for one alpha-thalassemia-2 chromosome, all were linked to the absence of an Rsa I restriction site located 0.7 kb 5' to the alpha 2-globin gene; this polymorphic site was observed for 10 of 38 non-alpha-thalassemia chromosomes from Black Americans. In four Black families with a heterozygous alpha-thalassemia-2 [-alpha 3.7 (I)], an Apa I restriction site has been identified in the IVS-2 of the alpha 2 gene of the normal chromosome (labeled the alpha *2 gene). The alpha *2 gene of one Black subject was cloned and a segment located 5' to the Cap site as well as the IVS-2, exon 3, and a 3' segment were sequenced. The data show that the alpha *2 gene is an alpha 2 gene except for a segment between nucleotides (nts) 580-81 and nt 509 (Cap site = nt 1), and perhaps as far upstream as nt -634, which has an alpha 1 sequence. This alpha *2 hybrid gene probably originated through a double crossover; the structural identity of its IVS-2 with that of the alpha 1 gene adequately explains the presence of the Apa I restriction site.
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PMID:Detection of a new hybrid alpha 2 globin gene among American blacks. 289 23

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


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