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The human erythrocyte membrane consists of a lipid bilayer containing transmembrane proteins and an underlying membrane skeleton, which is attached to the bilayer by linker protein complexes. The membrane is critical in maintaining the unique biconcave disk shape of the erythrocyte and enabling it to withstand the circulatory shear stress. The integrity of the membrane is ensured by vertical interactions between the skeleton and the transmembrane proteins, as well as by horizontal interactions between skeletal proteins. Inherited defects of membrane proteins compromise these interactions and alter the shape and deformability of the cells, which ultimately results in their premature destruction and hemolytic anemia. The disorders are typically autosomal dominant and exhibit significant clinical, laboratory, biochemical, and genetic heterogeneity.

Hereditary spherocytosis is a common condition characterized by spherically shaped erythrocytes on the blood film, reticulocytosis, and splenomegaly. The underlying defect is a deficiency of one of the membrane proteins, including ankyrin, band 3, α-spectrin, β-spectrin, or protein 4.2. This weakens the vertical membrane interactions, resulting in loss of membrane and surface area. Spherocytes have diminished deformability, which predisposes them to entrapment and destruction in the spleen. Hereditary elliptocytosis is characterized by the presence of elliptical erythrocytes on the blood film. The principal abnormality affects horizontal membrane protein interactions and typically involves α-spectrin, β-spectrin, protein 4.1R, or glycophorin C. The membrane skeleton is destabilized and unable to maintain the biconcave disk shape, which manifests as an elliptical distortion of the cells in the circulation. Hereditary pyropoikilocytosis is a rare, severe hemolytic anemia characterized by markedly abnormal erythrocyte morphology caused by defective spectrin. Southeast Asian ovalocytosis is largely asymptomatic and is caused by a defect in band 3. The blood film shows large oval red cells with a transverse ridge across the central area. Acanthocytosis is typified by contracted, dense erythrocytes with irregular projections, which may be seen in patients with severe liver disease, abetalipoproteinemia, various neurologic disorders, certain aberrant red cell antigens, and postsplenectomy. Stomatocytosis is a rare group of inherited disorders associated with abnormal membrane permeability and red cell cation content, which either cause overhydration or dehydration of the cells.


Acronyms and Abbreviations:

AE1, anion exchanger-1; αLELY, α-spectrin low-expression Lyon; αLEPRA, α-spectrin low-expression Prague; AGLT, acidified glycerol lysis test; ANK, ankyrin; AQP1, aquaporin-1; BCSH, British Committee for Standards in Haematology; BPG, 2,3-bisphosphoglycerate; CDAII, congenital dyserythropoietic anemia type II; EMA, eosin 5′-maleimide; 4.1R, erythrocyte isoform of protein 4.1; GLT, glycerol lysis test; GLUT-1, glucose transporter-1; GP, glycophorin; GP-A, -B, -C, -D, -E, various members of glycophorin family; GSSG, oxidized glutathione; HARP, hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration syndrome; HE, hereditary elliptocytosis; HPP, hereditary pyropoikilocytosis; HS, hereditary spherocytosis; HSt, hereditary stomatocytosis; MAGUK, membrane-associated guanylate kinase; MARCKS, myristoylated alanine-rich C kinase substrate; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; OF, osmotic fragility; PKAN, pantothenate kinase-associated neurodegeneration; RhAG, Rh-associated glycoprotein; SAO, southeast Asian ovalocytosis; SDS-PAGE, sodium dodecylsulfate polyacrylamide gel electrophoresis; ...

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