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ABSTRACT

  • The red-blood-cell membrane is composed of a bilayer of lipids and integral membrane proteins laminated to an underlying protein skeleton. The membrane skeleton is a two-dimensional meshwork of spectrin tetramers and oligomers cross-linked by protein 4.1 and short actin filaments. It is attached to the membrane via the binding of spectrin to ankyrin and ankyrin to band 3 protein and via an interaction between protein 4.1 and glycophorin C. The membrane skeleton is a major determinant of membrane shape, strength, and flexibility and helps to control lipid organization and integral protein mobility and topography. Genetic defects in the red cell membrane or its skeleton cause congenital hemolytic disorders or inherited abnormalities in red cell morphology such as hereditary elliptocytosis and hereditary spherocytosis.

  • Hereditary elliptocytosis (HE) is a heterogeneous group of congenital red cell disorders characterized by ellipsoidally shaped cells. Hereditary pyropoikilocytosis (HPP) is a related and more severe group of disorders characterized by fragmented red cells and poikilocytes. The clinical phenotypes of HE and HPP are a continuous spectrum with varying degrees of severity. Common HE is usually a mild, dominantly inherited condition with prominent elliptocytosis but little or no hemolysis. Acute hemolytic episodes sometimes occur in patients when splenomegaly develops in response to exogenous stimuli. Some patients with common HE present with poikilocytosis and hemolysis in infancy but later improve and are clinically mild after the first year of life. In the occasional patients with homozygous HE, severe hemolysis is observed. Similar features are observed in HPP, an uncommon, usually sporadic disorder manifest by severe hemolysis, marked poikilocytosis, and increased sensitivity of red cells to heat-induced fragmentation. HPP patients often have family members who have common HE, and their severe phenotype can be explained by the coinheritance of an HE allele and a disease-modifying gene.

  • Many defects in membrane skeletal proteins have been identified in patients with HE and HPP. Isolated skeletons from these patients retain the elliptocytic or poikilocytic shape of the original red cells, indicating that the defect causing the abnormal shape is intrinsic to the membrane skeleton. Many HE/HPP patients have spectrins that are heat-sensitive and defective in spectrin tetramer formation, and that cleave abnormally with proteases. Molecular analysis often demonstrate point mutations or small deletions in the α- or β-spectrin genes that interfere with tetramer formation. A low-expression α-spectrin allele, αLELY spectrin, is found at a high frequency in most populations. When αLELY spectrin is coinherited in trans to an HE α-spectrin allele, it markedly aggravates the clinical severity of the disease, explaining the sporadic occurrence of clinically severe HPP patients in common HE families. Other HE/HPP patients have deficient or abnormal protein 4.1 that weakens the skeleton protein meshwork. A small number of patients with very mild HE have glycophorin C deficiency.

  • Hereditary spherocytosis (HS) is a congenital hemolytic anemia characterized by spheroidally shaped red cells with a reduced surface area-to-volume ratio, due to a progressive loss of the plasma membrane. These spherocytes are ...

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