scholarly journals Disorders of the erythrocyte membrane

2015 ◽  
Vol 9 (4) ◽  
pp. 323
Author(s):  
Sophia Delicou ◽  
Aikaterini Xydaki ◽  
Chryssanthi Kontaxi ◽  
Konstantinos Maragkos
Keyword(s):  
Surface Area ◽  
Erythrocyte Membrane ◽  
Structural Integrity ◽  
Mechanical Stability ◽  
Hereditary Spherocytosis ◽  
Membrane Surface ◽  
Membrane Skeleton ◽  
Inherited Disorders ◽  
Hereditary Elliptocytosis ◽  
Area Loss

Hemolytic anemia due to abnormalities of the erythrocyte membrane comprises an important group of inherited disorders. These include hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, and the hereditary stomatocytosis syndromes. The erythrocyte membrane skeleton composed of spectrin, actin, and several other proteins is essential for the maintenance of the erythrocyte shape, reversible deformability, and membrane structural integrity in addition to controlling the lateral mobility of integral membrane proteins. These disorders are characterized by clinical and laboratory heterogeneity and, as evidenced by recent molecular studies, by genetic heterogeneity. Defects in various proteins involved in linking the lipid bilayer to membrane skeleton result in loss in membrane cohesion leading to surface area loss and hereditary spherocytosis while defects in proteins involved in lateral interactions of the spectrin-based skeleton lead to decreased mechanical stability, membrane fragmentation and hereditary elliptocytosis. The disease severity is primarily dependent on the extent of membrane surface area loss. Treatment with splenectomy is curative in most patients.

Mild spherocytic hereditary elliptocytosis and altered levels of α- and γ-adducins in β-adducin-deficient mice

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3978-3985 ◽  
Author(s):  
Andrés F. Muro ◽  
Martı́n L. Marro ◽  
Srećko Gajović ◽  
Fabiola Porro ◽  
Lucio Luzzatto ◽  
...  
Keyword(s):  
Membrane Surface ◽  
Osmotic Fragility ◽  
Membrane Skeleton ◽  
Blood Film ◽  
Mean Corpuscular Hemoglobin ◽  
Messenger Rnas ◽  
Inherited Disorders ◽  
Erythrocyte Morphology ◽  
Mild Phenotype ◽  
Hereditary Elliptocytosis

Abstract The membrane skeleton, a dynamic network of proteins associated with the plasma membrane, determines the shape and mechanical properties of erythrocytes. Deficiencies or defects in membrane skeletal proteins are associated with inherited disorders of erythrocyte morphology and function. Adducin is one of the proteins localized at the spectrin-actin junction of the membrane skeleton. In this work we show that deficiency of β-adducin produces an 80% decrease of -adducin and a fourfold up-regulation of γ-adducin in erythrocytes. β-Adducin or any other isoform generated by translation of abnormally spliced messenger RNAs could not be detected by our antibodies either in ghosts or in cytoplasm of −/− erythrocytes. Actin levels were diminished in mutant mice, suggesting alterations in the actin-spectrin junctional complexes due to the absence of adducin. Elliptocytes, ovalocytes, and occasionally spherocytes were found in the blood film of −/− mice. Hematological values showed an increase in reticulocyte counts and mean corpuscular hemoglobin concentration, decreased mean corpuscular volume and hematocrit, and normal erythrocyte counts that, associated to splenomegaly, indicate that the mice suffer from mild anemia with compensated hemolysis. These modifications are due to a loss of membrane surface and dehydration that result in an increase in the osmotic fragility of red blood cells. The marked alteration in osmotic fragility together with the predominant presence of elliptocytes is reminiscent of the human disorder called spherocytic hereditary elliptocytosis. Our results suggest that the amount of adducin remaining in the mutant animals (presumably γ adducin) could be functional and might account for the mild phenotype.

Mild spherocytic hereditary elliptocytosis and altered levels of α- and γ-adducins in β-adducin-deficient mice

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3978-3985 ◽  
Author(s):  
Andrés F. Muro ◽  
Martı́n L. Marro ◽  
Srećko Gajović ◽  
Fabiola Porro ◽  
Lucio Luzzatto ◽  
...  
Keyword(s):  
Membrane Surface ◽  
Osmotic Fragility ◽  
Membrane Skeleton ◽  
Blood Film ◽  
Mean Corpuscular Hemoglobin ◽  
Messenger Rnas ◽  
Inherited Disorders ◽  
Erythrocyte Morphology ◽  
Mild Phenotype ◽  
Hereditary Elliptocytosis

The membrane skeleton, a dynamic network of proteins associated with the plasma membrane, determines the shape and mechanical properties of erythrocytes. Deficiencies or defects in membrane skeletal proteins are associated with inherited disorders of erythrocyte morphology and function. Adducin is one of the proteins localized at the spectrin-actin junction of the membrane skeleton. In this work we show that deficiency of β-adducin produces an 80% decrease of -adducin and a fourfold up-regulation of γ-adducin in erythrocytes. β-Adducin or any other isoform generated by translation of abnormally spliced messenger RNAs could not be detected by our antibodies either in ghosts or in cytoplasm of −/− erythrocytes. Actin levels were diminished in mutant mice, suggesting alterations in the actin-spectrin junctional complexes due to the absence of adducin. Elliptocytes, ovalocytes, and occasionally spherocytes were found in the blood film of −/− mice. Hematological values showed an increase in reticulocyte counts and mean corpuscular hemoglobin concentration, decreased mean corpuscular volume and hematocrit, and normal erythrocyte counts that, associated to splenomegaly, indicate that the mice suffer from mild anemia with compensated hemolysis. These modifications are due to a loss of membrane surface and dehydration that result in an increase in the osmotic fragility of red blood cells. The marked alteration in osmotic fragility together with the predominant presence of elliptocytes is reminiscent of the human disorder called spherocytic hereditary elliptocytosis. Our results suggest that the amount of adducin remaining in the mutant animals (presumably γ adducin) could be functional and might account for the mild phenotype.

Temporal differences in membrane loss lead to distinct reticulocyte features in hereditary spherocytosis and in immune hemolytic anemia

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 2894-2899 ◽  
Author(s):  
Lydie Da Costa ◽  
Narla Mohandas ◽  
Martin Sorette ◽  
Marie-José Grange ◽  
Gil Tchernia ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Area ◽  
Hemolytic Anemia ◽  
Hereditary Spherocytosis ◽  
Membrane Surface ◽  
Red Cells ◽  
Membrane Surface Area ◽  
Temporal Differences ◽  
Cell Surface Area ◽  
Area Loss

Abstract Spherocytic red cells with reduced membrane surface area are a feature of hereditary spherocytosis (HS) and some forms of autoimmune hemolytic anemia (AIHA). It is generally assumed that membrane loss in spherocytic red cells occurs during their sojourn in circulation. The structural basis for membrane loss in HS is improper assembly of membrane proteins, whereas in AIHA it is due to partial phagocytosis of circulating red cells by macrophages. A hypothesis was formed that these different mechanisms should lead to temporal differences in surface area loss during red cell genesis and during sojourn in circulation in these 2 spherocytic syndromes. It was proposed that cell surface loss could begin at the reticulocyte stage in HS, whereas surface area loss in AIHA involves only circulating mature red cells. The validity of this hypothesis was established by documenting differences in cellular features of reticulocytes in HS and AIHA. Using a novel technique to quantitate cell surface area, the decreased membrane surface area of both reticulocytes and mature red cells in HS compared with normal cells was documented. In contrast, in AIHA only mature red cells but not reticulocytes exhibited decreased membrane surface area. These data imply that surface area loss in HS, but not in AIHA, is already present at the circulating reticulocyte stage. These findings imply that loss of cell surface area is an early event during genesis of HS red cells and challenge the existing concepts that surface area loss in HS occurs predominantly during the sojourn of mature red cells in circulation.

scholarly journals Anion Exchanger 1 (Band 3) Is Required to Prevent Erythrocyte Membrane Surface Loss but Not to Form the Membrane Skeleton

Cell ◽  
1996 ◽  
Vol 86 (6) ◽  
pp. 917-927 ◽  
Author(s):  
Luanne L Peters ◽  
Ramesh A Shivdasani ◽  
Shih-Chun Liu ◽  
Manjit Hanspal ◽  
Kathryn M John ◽  
...  
Keyword(s):  
Erythrocyte Membrane ◽  
Anion Exchanger ◽  
Membrane Surface ◽  
Membrane Skeleton ◽  
Band 3 ◽  
Anion Exchanger 1 ◽  
Surface Loss

Hereditary elliptocytosis due to both qualitative and quantitative defects in membrane skeletal protein 4.1

Blood ◽  
1991 ◽  
Vol 78 (9) ◽  
pp. 2438-2443 ◽  
Author(s):  
JG Conboy ◽  
R Shitamoto ◽  
M Parra ◽  
R Winardi ◽  
A Kabra ◽  
...  
Keyword(s):  
Amino Acids ◽  
Mechanical Stability ◽  
Membrane Skeleton ◽  
Actin Binding ◽  
Erythrocyte Morphology ◽  
Protein 4.1 ◽  
Hereditary Elliptocytosis ◽  
Exon Expression ◽  
Amino Acid Peptide ◽  
Skeletal Protein

Abstract Protein 4.1 is an important structural component of the membrane skeleton that helps determine erythrocyte morphology and membrane mechanical properties. In a previous study we identified a case of human hereditary elliptocytosis (HE) in which decreased membrane mechanical stability was due to deletion of 80 amino acids encompassing the entire 10-Kd spectrin-actin binding domain. A portion of this domain (21 amino acids) is encoded by an alternatively spliced exon that is expressed in late but not early erythroid cells. We now report a case of canine HE in which the abnormal phenotype is caused by failure to express this alternative peptide in the mature red blood cell (RBC) membrane skeleton, in conjunction with quantitative deficiency of protein 4.1. Western blotting of RBC membranes from a dog with HE showed a truncated protein 4.1 that did not react with antibodies directed against the alternative peptide. In addition, sequencing of cloned reticulocyte protein 4.1 cDNA showed a precise deletion of 63 nucleotides comprising this exon. Normal dog reticulocytes did express this exon. Expression of this 21 amino acid peptide during erythroid maturation is therefore essential for proper assembly of a mechanically competent membrane skeleton, because RBCs lacking this peptide have unstable membranes.

scholarly journals Identification of a Novel Role for Dematin in Regulating Red Cell Membrane Function by Modulating Spectrin-Actin Interaction

2012 ◽  
Vol 287 (42) ◽  
pp. 35244-35250 ◽  
Author(s):  
Ichiro Koshino ◽  
Narla Mohandas ◽  
Yuichi Takakuwa
Keyword(s):  
Erythrocyte Membrane ◽  
Quartz Crystal ◽  
Mechanical Stability ◽  
Membrane Skeleton ◽  
Tail Region ◽  
Red Cell Membrane ◽  
Membrane Function ◽  
Pulldown Assay ◽  
Optimal Functioning ◽  
Protein 4.1R

The membrane skeleton plays a central role in maintaining the elasticity and stability of the erythrocyte membrane, two biophysical features critical for optimal functioning and survival of red cells. Many constituent proteins of the membrane skeleton are phosphorylated by various kinases, and phosphorylation of β-spectrin by casein kinase and of protein 4.1R by PKC has been documented to modulate erythrocyte membrane mechanical stability. In this study, we show that activation of endogenous PKA by cAMP decreases membrane mechanical stability and that this effect is mediated primarily by phosphorylation of dematin. Co-sedimentation assay showed that dematin facilitated interaction between spectrin and F-actin, and phosphorylation of dematin by PKA markedly diminished this activity. Quartz crystal microbalance measurement revealed that purified dematin specifically bound the tail region of the spectrin dimer in a saturable manner with a submicromolar affinity. Pulldown assay using recombinant spectrin fragments showed that dematin, but not phospho-dematin, bound to the tail region of the spectrin dimer. These findings imply that dematin contributes to the maintenance of erythrocyte membrane mechanical stability by facilitating spectrin-actin interaction and that phosphorylation of dematin by PKA can modulate these effects. In this study, we have uncovered a novel functional role for dematin in regulating erythrocyte membrane function.

scholarly journals Analysis of Integral Membrane Protein Contributions to the Deformability and Stability of the Human Erythrocyte Membrane

2001 ◽  
Vol 276 (50) ◽  
pp. 46968-46974 ◽  
Author(s):  
Heidi M. Van Dort ◽  
David W. Knowles ◽  
Joel A. Chasis ◽  
Gloria Lee ◽  
Narla Mohandas ◽  
...  
Keyword(s):  
Surface Area ◽  
Erythrocyte Membrane ◽  
Human Erythrocyte ◽  
Membrane Skeleton ◽  
Band 3 ◽  
Membrane Stability ◽  
Human Erythrocyte Membrane ◽  
Lipid Interactions ◽  
Membrane Spanning ◽  
The Impact

Three major hypotheses have been proposed to explain the role of membrane-spanning proteins in establishing/maintaining membrane stability. These hypotheses ascribe the essential contribution of integral membrane proteins to (i) their ability to anchor the membrane skeleton to the lipid bilayer, (ii) their capacity to bind and stabilize membrane lipids, and (iii) their ability to influence and regulate local membrane curvature. In an effort to test these hypotheses in greater detail, we have modified both the membrane skeletal and lipid binding interactions of band 3 (the major membrane-spanning and skeletal binding protein of the human erythrocyte membrane) and have examined the impact of these modifications on erythrocyte membrane morphology, deformability, and stability. The desired changes in membrane skeletal and protein-lipid interactions were induced by 1) reaction of the cells with 4,4′-diisothiocyanostilbene-2,2′-disulfonate (DIDS), an inhibitor of band 3-mediated anion transport that dissociates band 3 into dimers (increasing its surface area in contact with lipid) and severs band 3 linkages to the membrane skeleton; 2) a fragment of ankyrin that ruptures the same ankyrin-band 3 bridge to the membrane skeleton, but drives the band 3 subunit equilibrium toward the tetramer (i.e.decreasing the band 3 surface area in contact with lipid); and 3) an antibody to the ankyrin-binding site on band 3 that promotes the same changes in band 3 skeletal and lipid interactions as the ankyrin fragment. We observed that although DIDS induced echinocytic morphological changes in the treated erythrocytes, it had little impact on either membrane deformability or stability. In contrast, resealing of either the ankyrin fragment or anti-band 3 IgG into erythrocytes caused spontaneous membrane fragmentation and loss of deformability/stability. Because these and other new observations cannot all be reconciled with any single hypothesis on membrane stability, we suggest that more than one hypothesis may be operative and provide an explanation of how each might individually contribute to net membrane stability.

scholarly journals Identification of a functional role for human erythrocyte sialoglycoproteins beta and gamma

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1068-1072
Author(s):  
ME Reid ◽  
JA Chasis ◽  
N Mohandas
Keyword(s):  
Erythrocyte Membrane ◽  
Material Properties ◽  
Functional Role ◽  
Mechanical Stability ◽  
Membrane Skeleton ◽  
Membrane Properties ◽  
Membrane Material ◽  
Skeletal Protein ◽  
Alpha Beta ◽  
Normal Erythrocyte

Four distinct erythrocyte membrane sialoglycoproteins (SGPs) denoted alpha, beta, gamma, and delta have been described, but their functions have not yet been defined. Recent evidence suggests that several of these SGPs associate with membrane skeletal proteins. Because the membrane skeletal protein network plays an important role in regulating the membrane material properties of deformability and mechanical stability, we wanted to determine whether the SGPs, through their interaction with the membrane skeleton, can modulate these membrane properties. We measured membrane mechanical stability and membrane deformability of erythrocytes that were deficient in either alpha, or delta or beta and gamma SGPs. Only erythrocytes deficient in beta and gamma SGP had altered membrane properties, as evidenced by marked decreases in both membrane mechanical stability (50% of normal) and membrane deformability (40% of normal). Erythrocytes deficient in either alpha or delta SGP had normal deformability and stability. Based on these data, we suggest that an interaction of beta and/or gamma SGP with the membrane skeleton plays a functionally important role in regulating normal erythrocyte membrane properties.

scholarly journals The distribution of erythrocyte phospholipids in hereditary spherocytosis demonstrates a minimal role for erythrocyte spectrin on phospholipid diffusion and asymmetry

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 1051-1057 ◽  
Author(s):  
FA Kuypers ◽  
BH Lubin ◽  
M Yee ◽  
P Agre ◽  
PF Devaux ◽  
...  
Keyword(s):  
Erythrocyte Membrane ◽  
Hereditary Spherocytosis ◽  
Phospholipid Composition ◽  
Membrane Skeleton ◽  
Erythrocyte Membranes ◽  
Minor Role ◽  
Membrane Phospholipids ◽  
Normal Range ◽  
Outer Leaflet ◽  
Kinetics Of

Abstract In the human erythrocyte membrane phosphatidylcholine and sphingomyelin reside mainly in the outer leaflet, whereas the aminophospholipids, phosphatidylethanolamine and phosphatidylserine, are mainly found in the inner leaflet. Maintenance of phospholipid asymmetry has been assumed to involve interactions between the aminophospholipids and the membrane skeleton, in particular spectrin. To investigate whether spectrin contributes to maintaining the phospholipid transbilayer distribution and kinetics of redistribution, we studied erythrocytes from hereditary spherocytosis patients whose spectrin levels ranged from 34% to 82% of normal. The phospholipid composition and the accessibility of membrane phospholipids to hydrolysis by phospholipases were in the normal range. Spin-labeled phosphatidylserine and phosphatidylethanolamine analogues that had been introduced into the outer leaflet were rapidly transported at 37 degrees C to the inner leaflet, whereas the redistribution of spin-labeled phosphatidylcholine was slower. The kinetics of transbilayer movement of these spin-labeled phospholipid in all samples was in the normal range and was not affected by the level of spectrin. Although these erythrocyte membranes contained as little as 34% of the normal level of spectrin and were characterized by several physical abnormalities, the composition, distribution, and transbilayer kinetics of the phospholipids were found to be normal. We therefore conclude that spectrin plays, at best, only a minor role in maintaining the distribution of erythrocyte membrane phospholipid.

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