Is Hemoglobin Instability Important in the Interaction Between Hemoglobin E and β Thalassemia?

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2141-2146 ◽  
Author(s):  
D.C. Rees ◽  
J.B. Clegg ◽  
D.J. Weatherall

Hemoglobin E (HbE; 2β226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous β thalassemia. Yet, when it is inherited together with a β thalassemia allele, the resulting condition, HbE/β thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the β thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37°C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/β thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/β+ thalassemia red blood cells age. Globin binding to membranes was assessed and only  globin chains were found, in contrast to other unstable hemoglobins in which both  and β chains were present. However, in experiments performed on blood from HbE/β thalassemics in the temperature range 39°C to 41°C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/β thalassemia is primarily the result of the interaction of two β thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia. © 1998 by The American Society of Hematology.

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2141-2146 ◽  
Author(s):  
D.C. Rees ◽  
J.B. Clegg ◽  
D.J. Weatherall

Abstract Hemoglobin E (HbE; 2β226glu-lys), globally the commonest hemoglobin variant, is synthesized at a slightly reduced rate and has a homozygous phenotype similar to heterozygous β thalassemia. Yet, when it is inherited together with a β thalassemia allele, the resulting condition, HbE/β thalassemia, is sometimes characterized by a severe, transfusion-dependent thalassemia major. The severity of this interaction has not been explained. We have explored the possibility that it may reflect the instability of HbE consequent upon globin chain imbalance imposed by the β thalassemia allele. Time-course and pulse-chase globin chain synthesis studies at 37°C on peripheral blood and bone marrow suggest that hemoglobin instability is not significant in steady-state HbE/β thalassemia; this is confirmed by density-gradient centrifugation studies that show no decrease in HbE levels relative to HbA as HbE/β+ thalassemia red blood cells age. Globin binding to membranes was assessed and only  globin chains were found, in contrast to other unstable hemoglobins in which both  and β chains were present. However, in experiments performed on blood from HbE/β thalassemics in the temperature range 39°C to 41°C, there was evidence of instability of HbE, a finding that was also observed in homozygous HbE. These findings suggest that the phenotype of HbE/β thalassemia is primarily the result of the interaction of two β thalassemia alleles; however, hemoglobin instability may be important during febrile episodes, contributing to worsening anemia. © 1998 by The American Society of Hematology.


Blood ◽  
1978 ◽  
Vol 51 (4) ◽  
pp. 653-658 ◽  
Author(s):  
RS Franco ◽  
JW Hogg ◽  
OJ Martelo

Abstract To define further the role of hemin-controlled repressor (HCR) in globin synthesis, we studied its effect on the synthesis of individual globin chains in a rabbit reticulocyte lysate cell-free system. In the presence of HCR there was a marked globin chain imbalance, resulting in a lowered alpha/beta ratio. These findings in vitro may have relevance to certain clinical heme deficiency states in which a similar globin chain imbalance has been observed.


Blood ◽  
1980 ◽  
Vol 56 (1) ◽  
pp. 93-97 ◽  
Author(s):  
T Terasawa ◽  
M Ogawa ◽  
PN Porter ◽  
JD Karam

Abstract We examined gamma-globin-chain biosynthesis by adult and umbilical cord blood or erythropoietic bursts in methylcellulose clonal culture and gamma-chain synthesis by cord blood reticulocytes. Globin chains were labeled with 14C-amino acids and guantitated by using autoradiography or fluorography. Alpha, beta, and G gamma and A gamma chains were separated by isoelectric focusing in polyacrylamide gels containing 8 M urea and 3% Nonidet P-40 (a nonionic detergent). Time course examinations of the gamma-chains synthesized by the bursts revealed no changes in the G gamma:A gamma ratio between days 10 and 18 of culture. The ratio of G gamma/(G gamma + A gamma) in cultures of adult circulating erythroid precursors was 0.38 +/- 0.09, which corresponds to the known ratio in adult peripheral blood erythrocytes. The relative G gamma-chain biosyntheses in the cord blood bursts and reticulocytes were 0.56 +/- 0.02 and 0.66 +/- .008, respectively. Both are intermediate between the accepted newborn and adult ratios. Natal erythropoietic precursors appear to be in the transitional stage with respect to the switching of G gamma-A gamma ratios.


Blood ◽  
1980 ◽  
Vol 56 (1) ◽  
pp. 93-97 ◽  
Author(s):  
T Terasawa ◽  
M Ogawa ◽  
PN Porter ◽  
JD Karam

We examined gamma-globin-chain biosynthesis by adult and umbilical cord blood or erythropoietic bursts in methylcellulose clonal culture and gamma-chain synthesis by cord blood reticulocytes. Globin chains were labeled with 14C-amino acids and guantitated by using autoradiography or fluorography. Alpha, beta, and G gamma and A gamma chains were separated by isoelectric focusing in polyacrylamide gels containing 8 M urea and 3% Nonidet P-40 (a nonionic detergent). Time course examinations of the gamma-chains synthesized by the bursts revealed no changes in the G gamma:A gamma ratio between days 10 and 18 of culture. The ratio of G gamma/(G gamma + A gamma) in cultures of adult circulating erythroid precursors was 0.38 +/- 0.09, which corresponds to the known ratio in adult peripheral blood erythrocytes. The relative G gamma-chain biosyntheses in the cord blood bursts and reticulocytes were 0.56 +/- 0.02 and 0.66 +/- .008, respectively. Both are intermediate between the accepted newborn and adult ratios. Natal erythropoietic precursors appear to be in the transitional stage with respect to the switching of G gamma-A gamma ratios.


Blood ◽  
1978 ◽  
Vol 51 (4) ◽  
pp. 653-658
Author(s):  
RS Franco ◽  
JW Hogg ◽  
OJ Martelo

To define further the role of hemin-controlled repressor (HCR) in globin synthesis, we studied its effect on the synthesis of individual globin chains in a rabbit reticulocyte lysate cell-free system. In the presence of HCR there was a marked globin chain imbalance, resulting in a lowered alpha/beta ratio. These findings in vitro may have relevance to certain clinical heme deficiency states in which a similar globin chain imbalance has been observed.


Blood ◽  
1972 ◽  
Vol 40 (1) ◽  
pp. 105-111 ◽  
Author(s):  
Mordechai Shchory ◽  
Bracha Ramot

Abstract α, β, and γ globin chain synthesis in bone marrow and peripheral blood reticulocytes were studied in two patients with thalassemia major, two with thalassemia intermedia, one with thalassemia minor, one with Hb H disease, and one with homozygous βδ-thalassemia. Nine nonthalassemic patients served as controls. In thalassemia major, a marked imbalance of α- to β-chain synthesis was found in the bone marrow as well as in reticulocytes. The imbalance, however, was slightly more evident in the latter. In the patients with thalassemia intermedia and minor the α- to β-globin chain ratios in the reticulocytes were of the same order of magnitude, despite the marked clinical differences between thalassemia intermedia and minor. A balanced synthesis was found in the bone marrow of the patient with thalassemia minor. The bone marrow globin synthesis in thalassemia intermedia was not studied. Contrary to that in Hb H disease and βδ-thalassemia, the imbalance was more apparent in the bone marrow. In the latter, no evidence for imbalance was detected in the reticulocytes. These results point out the need for further studies on globin chain synthesis in the bone marrow and reticulocytes of patients With the various thalassemia syndromes and the effect of the free globin chain pool on those results.


Blood ◽  
1976 ◽  
Vol 47 (1) ◽  
pp. 113-120 ◽  
Author(s):  
RF Rieder

Abstract A 23-yr-old man of Greek-Italian ancestry with mild anemia was found to be heterozygous for HbD (Punjab) beta121 glu leads to gin and beta- thalassemia. HbA was not detected upon electrophoresis of the subject's hemolysate, and no synthesis of betaA globin was demonstrated after incubation of peripheral blood or bone marrow with 3H-leucine. The thalassemia gene was thus of the betao variety. The betaD/alpha synthesis ratios were almost equally unbalanced in the blood and bone marrow: 0.53 and 0.61, respectively. The mother of the propositus had beta-thalassemia trait. In peripheral blood the betaA/alpha synthesis ratio was 0.38. The mutant betaD gene thus appeared potentially capable of directing the synthesis of globin chains as efficiently as a normal betaA gene. The mildness of the HbD-betao-thalassemia syndrome appeared to be due to the maintenance of a relatively high total beta/alpha synthesis ratio in the presence of a physiologically neutral structural mutation.


Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Swee Lay Thein

Abstract The central mechanism underlying the pathophysiology of the β thalassemias can be related to the deleterious effects of imbalanced globin chain synthesis on erythroid maturation and survival. An imbalance of the α/non-α globin chains leads to an excess of unmatched α globin which precipitates out, damaging membrane structures leading to accelerated apoptosis and premature destruction of the erythroid precursors in the bone marrow (ineffective erythropoiesis). Close observation of the genotype/phenotype relationships confirms the pathophysiological mechanism and provides clues to molecular therapies, all of which aim to reduce the α/non-α chain imbalance. They include inheritance of the milder forms of β thalassemia, co-inheritance of α thalassemia, or genetic factors (quantitative trait loci, QTLs) for increasing γ globin expression. Currently, the most promising molecular therapeutic approaches include increasing β globin gene expression by stem cell gene therapy and increasing γ globin expression using pharmacological agents or by transduction of the γ globin genes.


Blood ◽  
1968 ◽  
Vol 31 (2) ◽  
pp. 226-233 ◽  
Author(s):  
ARTHUR BANK ◽  
ALBERT S. BRAVERMAN ◽  
JOYCE V. O’DONNELL ◽  
PAUL A. MARKS

Abstract The absolute rate of α chain synthesis per erythroid cell in the peripheral blood of patients with β thalassemia has been shown to be normal while that of β chains is markedly decreased or absent. The results indicate that α chains do not require the presence of β chains for their normal synthesis and release. In addition, γ chain synthesis does not compensate for the decreased β chain synthesis. A marked heterogeneity in the amount of β globin chains produced by different patients with β thalassemia is also prominent.


Hemoglobin ◽  
1982 ◽  
Vol 6 (1) ◽  
pp. 75-78 ◽  
Author(s):  
P. Wasi ◽  
P. Winichagoon ◽  
T. Baramee ◽  
S. Fucharoean

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