γ‐mRNA and Hb F levels in <i>β</i>‐thalassaemia

Efremov, D. G.; Dimovski, Aleksandar; Sukarova, E.; Schilirò, Gino; Zisovski, N; Ефремов, Г. Д.; Burrone, Óscar R.; Huisman, T. H. J.

doi:10.1111/j.1365-2141.1994.tb05024.x

Cited by 24 publications

(18 citation statements)

References 22 publications

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“…38 The relative amounts of γ-and -mRNA were determined by RT-PCR methodology described in detail by Efremov 39 in thalassaemia major and -thal intermedia patients.…”

Section: Rna Analysismentioning

confidence: 99%

Nucleotide changes in the γ-globin promoter and the (AT)xNy(AT)z polymorphic sequence of βLCRHS-2 region associated with altered levels of HbF

et al. 1999

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We have studied 31 -thalassaemia intermedia, 30 -thalassaemia major patients and 50 normal individuals from Turkey, determining the relationship between the nucleotide variations in -globin gene cluster, the altered levels of foetal haemoglobin and the relative ratios of -and γ mRNAs. We have found in -thalassaemia intermedia patients with high foetal haemoglobin expression that the three nucleotide variations in the 5' sequences of the gamma globin genes, A→G at Gγ -1396, the T→C at Aγ -228, and the GA→AG at Aγ -603/4, are linked to haplotype II in haplotypic homozygotes and the (AT) 8 N 14 (AT) 7 motif in LCR. Conversely, the three single nucleotide substitutions in the 5' sequences of gamma globin genes, the G→A at Gγ -1225, the A→G at Aγ + 25 and the C→G at Aγ -369, which have a strong linkage with haplotype I, V or VI in haplotypic homozygotes and the (AT) 10 N 12 (AT) 12 and the (AT) 9 N 12 (AT) 12 motifs in HS-2 of LCR are all associated with low foetal haemoglobin levels. The number of nucleotide changes in -globin gene cluster implied in our study are not the primary cause of the differences in haemoglobin F levels. They perhaps may contribute to the variations in the clinical severity observed among thalassaemia intermedia and major patients with other yet unknown gene conversions.

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“…38 The relative amounts of γ-and -mRNA were determined by RT-PCR methodology described in detail by Efremov 39 in thalassaemia major and -thal intermedia patients.…”

Section: Rna Analysismentioning

confidence: 99%

Nucleotide changes in the γ-globin promoter and the (AT)xNy(AT)z polymorphic sequence of βLCRHS-2 region associated with altered levels of HbF

et al. 1999

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“…These may be the mechanisms which normally contribute, in addition to decreased transcription, to the reduced expression of HbA 2 , namely decreased mRNA stability or decreased translational efficiency. The recent finding of higher ratios of γ-mRNA to HbF levels in peripheral blood erythroid cells from adults as compared to newborns suggests a corresponding mechanism for the control of HbF [17]. The known reciprocal control of the transcription of the γ- and β-globin genes [18, 19]through competitive interactions with the locus control regions may contribute to an increased transcription of the other β-like genes (δ or γ) when the β-globin gene transcription is repressed.…”

Section: Discussionmentioning

confidence: 99%

The Delta-Globin RNA Transcript Level in Beta-Thalassemia Carriers

Huang

Zeng²,

Chen³

et al. 1999

Acta Haematol

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Increased levels of hemoglobin A₂ (HbA₂) are present in most β-thalassemia carriers. The mechanism of this effect is not understood, although the increase may result from transcriptional and posttranscriptional changes. In the present study, we quantitate δ-globin mRNA levels in peripheral-blood-enriched reticulocytes and characterize the variation of δ-mRNA levels in 30 β-thalassemia heterozygotes who individually carry one of the four common Chinese β-thalassemia alleles [codons 41/42 (–TTCT); codon 17 (A→T); IVS-II-654 (C→T); –28 (A→G)]. A sensitive and quantitative competitive reverse-transcriptase polymerase chain reaction method was developed and used to assess the absolute amounts of δ-mRNA transcripts in these peripheral erythroid cells. The results showed a large increase in δ-mRNA amounts in all the carriers examined (72.3 ± 9.0 amol/μg RNA) as compared with those in 12 controls (1.2 ± 0.2 amol/ μg RNA). There was a direct correlation between the δ-mRNA levels and types of β-thalassemia alleles; generally, the δ-mRNA levels are higher in heterozygotes for β⁰-thalassemia mutations than β⁺-thalassemia mutations. The δ-mRNA levels correlated inversely with hemoglobin and red cell indices but directly with HbA₂ levels in heterozygotes of each of the group of β-thalassemia mutations. These results suggest that a greater impairment in β-globin gene expression results in increased transcription of δ-globin gene and in a higher level of HbA₂.

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“…Deter mination of the a2/al, the a/p, and the y/p ratios is based on RT-PCR methodology described in detail by Efremov et al [9,10], by Molchanova et al [14], and by Smetanina et al [15]. …”

Section: Methodsmentioning

confidence: 99%

“…As a result, both (3°-or (P-thal occur. In (3+-thal, P-chain synthesis remains but at a markedly reduced rate and there is a cor respondingly reduced level of P-globin messenger RNA (mRNA) in reticulocytes [3,4], No P-chains are synthe sized in P°-thal, and early studies of the globin mRNA in this condition demonstrated a heterogeneity at the molec ular level [5][6][7][8], Recent development of methodology involving a re verse transcriptase-polymerase chain reaction (RT-PCR) procedure provides a useful and sensitive technique for the study of gene expression [9][10][11][12][13][14] because this RT-PCR method makes it simple to analyze the relative quantities of the globin mRNAs in human reticulocytes. We have used this method to quantitate the relative levels of a-and P-globin mRNA in a-thal patients [15].…”

mentioning

confidence: 99%

Globin mRNA in β-Thalassemia Heterozygotes with Different β-Thalassemia Alleles and in Heterozygotes for Hereditary Persistence of Fetal Hemoglobin

1996

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Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to determine the α2/α1-, α/β-, and γ/β-mRNA ratios in subjects with β -thalassemia (β-thal), hereditary persistence of fetal hemoglobin (HPFH), and normal adults. The α- and β -globin gene mutations were characterized with gene mapping, PCR, and DNA sequencing. The average α2/α1-mRNA ratio was the same in normal adults and β-thal heterozygotes with four α-globin genes (2.61-2.63) or with an α-thal-2 trait (1.48-1.55). The average α/β -mRNA ratios were 4.47 and 3.84 in normal adults with four α-globin genes and with α-thal-2 trait (-α/αα), respectively. There was an increase of ∼ 50% in ιs β -thal heterozygotes with transcriptional mutants [-88 (C→T) and -29 (A→G)] with lower alues (∼ 25%) in those with α-thal-2 trait (-α/αα). High α/β ratios were also observed for heterozygotes for nonsense or frameshift mutants located in exon 1 or exon 2. Increases of -150-165% were seen in subjects with RNA processing defects; an exception was the IVS-I-110 (G→ A) mutation with a normal value in the heterozygote. The increases were also less pronounced in heterozygotes for the codon (CD) 121 (G→T) mutation and the CDs 134-137 insertion/deletion. Normal α/(γ+β) values were seen in 3 heterozygotes each with a different deletion involving part of the β -globin gene. The presence of the silent β -thal allele, -101 (C→T), in trans to a CD 8 (-AA) allele has a minor effect on the α/β-mRNA ratio. The α/β -mRNA ratio in HPFH heterozygotes was ∼ 145% of normal, but with a γ-mRNA level of 35.4-44.7% the calculated α/(γ+β) ratio became as in normal adults. The RT-PCR methodology appears useful in expression studies in β -thal (and HPFH) and values of mRNA appear to correspond to the type of prevailing mutation(S) and concomitant α-thal.

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γ‐mRNA and Hb F levels in β‐thalassaemia

Cited by 24 publications

References 22 publications

Nucleotide changes in the γ-globin promoter and the (AT)xNy(AT)z polymorphic sequence of βLCRHS-2 region associated with altered levels of HbF

Nucleotide changes in the γ-globin promoter and the (AT)xNy(AT)z polymorphic sequence of βLCRHS-2 region associated with altered levels of HbF

The Delta-Globin RNA Transcript Level in Beta-Thalassemia Carriers

Globin mRNA in β-Thalassemia Heterozygotes with Different β-Thalassemia Alleles and in Heterozygotes for Hereditary Persistence of Fetal Hemoglobin

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