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May band 3 hyper-phosphorylation have a functional role in microcyte formation in heterozygous thalassemias?

Ferru, Emanuela and Pantaleo, Antonella and Mannu, Franca Rita and Carta, Franco and Turrini, Francesco Michelangelo (2010) May band 3 hyper-phosphorylation have a functional role in microcyte formation in heterozygous thalassemias? Blood Cells, Molecules, and Diseases, Vol. 45 (1), p. 65-66. eISSN 1096-0961. Article.

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DOI: 10.1016/j.bcmd.2010.02.018

Abstract

Heterozygous alpha and beta thalassemia are extremely frequent in malaria endemic areas displaying a well balanced hematological situation with very mild anemia and microcytic red cells. There is widespread consensus that thalassemia determines resistance to severe malaria although the molecular basis of the mechanism of resistance is not understood. A few studies indicate that the thalassemic cell environment does not directly harm the parasites but apparently induces the loss of viability of infected red cells and their enhanced removal by macrophages. The difficulty to develop an hypothesis on the mechanism of malaria resistance largely derives from the substantial lack of knowledge on the physiology of thalassemic red cells in heterozygotes. Although causing only mild and asymptomatic anemia, the genetic defect causes unbalanced hemoglobin chain production. It is not understood how this large excess of globin chains can be removed without effecting the viability of the red cell. It is generally accepted that the loss of red cell membrane leading to microcytosis may represent the counterpart of hemoglobin chain excess removal but the mechanisms underlying this process are not defined. Our previous observations showed that in splenectomized intermediate thalassemia patients the Hb increase (from 7.7 to 9.1 g/dl) in comparison to non-splenectomized patients was due to a net increase of mean MCV (from 71 to 82 fl) and not to an increased number of red cells. This clinical evidence is not, therefore, in accordance with the concept that, in thalassemia, the spleen mainly acts to remove altered red cells but suggests that the spleen has an active role in reducing red cell volume. We have observed a larger amount of hemichromes bound to the red cell membrane in splenectomised patients. Those data are an indication that splenic macrophages exert a role in removing the hemichromes leading to a decrease of red cell volume. Histological studies show the role of splenic macrophages in “pitting” part of the red cell membrane containing hemichromes.
Based on some recently published results and some preliminary data we developed the hypothesis that a physiological mechanism may permit the removal of abnormal globins deposited on the cytoplasmic side of the red cell membrane. This process should require a series of sequential events:
a) binding of denatured globin chains to specific membrane protein ligands
b) selective modification of the ligand bound to the globins to induce its clustering and the accumulation of all globin excess in a limited area of the membrane
c) some mechanism leading to the recognition and binding of the clustered globin ligand by macrophages
d) weakening of membrane structure in the area of denatured globin accumulation to allow its selective removal by macrophages and/or vesiculation of locally destabilized areas without interfering with the overall integrity of red cell membrane.
This mechanism should allow globin excess removal minimizing the area of the membrane to be sacrificed therefore obtaining smaller but still viable biconcave red cells.

Item Type:Article
ID Code:5777
Status:Published
Refereed:Yes
Uncontrolled Keywords:Heterozygous alpha, beta thalassemia, microcytosis, protein phosphorylation, erythrocyte band 3 protein
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:002 Altri enti e centri di ricerca del Nord Sardegna > Nurex Bioresearch Sassari, Sassari
Publisher:Academic Press / Elsevier
eISSN:1096-0961
Copyright Holders:© 2010 Elsevier
Deposited On:22 Mar 2011 10:25

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