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The human erythrocyte membrane consists of a lipid bilayer containing transmembrane proteins and an underlying membrane skeleton that 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 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, seen clinically as hemolytic anemia. The disorders are typically inherited in an autosomal dominant manner and exhibit significant clinical, laboratory, biochemical and genetic heterogeneity.

Hereditary spherocytosis (HS) 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, anion exchanger-1 (AE1, formerly band 3), α-spectrin, β-spectrin, or protein 4.2. These defects weaken 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 (HE) 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 (HPP) is a rare, severe hemolytic anemia characterized by markedly abnormal erythrocyte morphology resulting from defective spectrin. South East Asian Ovalocytosis (SAO) is largely asymptomatic and is caused by a defect in AE1. 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:

αLELY, α-spectrin low-expression Lyon; αLEPRA, α-spectrin low-expression Prague; AE1, anion exchanger-1 (formerly band 3); AGLT, acidified glycerol lysis test; ANK1, ankyrin gene; ANK, ankyrin; apo-B, apolipoprotein B; ATP11C, P-IV ATPase (flippase); AQP1, aquaporin-1; BPG, bisphosphoglycerate; CDAII, congenital dyserythropoietic anemia type II; DAT, direct antiglobulin test; DI, deformability index; EMA, eosin 5′maleimide; G3PD, glyceraldehyde 3-phosphate dehydrogenase; 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; HAc, hereditary acanthocytosis; HDL2, Huntington Disease-Like 2; HE, hereditary elliptocytosis; HPP, hereditary pyropoikilocytosis; HS, hereditary spherocytosis; HSt, hereditary stomatocytosis; ICSH, International Council on Standardization in Haematology; JPH3, Junctophilin-3 gene; KCNN4, Potassium Calcium-activated channel subfamily N member 4 gene; MAGUK, membrane-associated guanylate kinase; MARCKS, myristylated alanine-rich C kinase ...

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