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INTRODUCTION

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LEARNING OBJECTIVES

After studying this chapter you should have a coherent understanding of:

  • The organization and function of the major proteins of the red cell membrane and cytoskeleton.

  • The pathogenesis and clinical features of hereditary spherocytosis.

  • The genetics and pathogenesis of glucose-6-phosphate dehydrogenase deficiency.

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DISORDERS OF THE RED CELL MEMBRANE

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MOLECULAR ANATOMY OF THE RED CELL MEMBRANE

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As mentioned in Chapter 1, the red cell has two relatively simple yet highly important responsibilities—the transport of oxygen from the lungs to respiring organs and tissues and the transport of carbon dioxide in the reverse direction. Because of its relatively long life span of 120 days, a single red cell makes about 170,000 circuits through the microcirculation and, in doing so, travels roughly 100 miles! The efficiency of both gas transport and flow through narrow channels in the capillary and splenic circulation is enhanced by the ability of the red cell to change shape. Thus, in order for a red cell to fulfill its functions, its membrane must have a high degree of durability and flexibility.

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The basis for the remarkable mechanical properties of the red cell is a network of proteins that assemble to form a specialized membrane skeleton, depicted in Figure 10-1. The primary building blocks of the membrane skeleton are alpha (α)-spectrin and beta (β)-spectrin, which bind to each other to form long, stable dimers. Self-association of spectrin dimers and docking of spectrin to a complex of actin filaments, with the aid of protein 4.1, creates a flexible, branching, hexagonal network that covers the entire inner surface of the membrane. The membrane skeleton is tethered to the membrane's lipid bilayer by vertical interactions with a complex composed of the anion exchange channel (band 3), ankyrin, and protein 4.2. These horizontal and vertical interactions within the membrane skeleton and with the lipid bilayer are critical determinants of the pliability and tensile strength of the red cell membrane.

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FIGURE 10-1

Cross-section of the red cell membrane. The membrane skeleton is composed principally of spectrin (green), which binds to itself at one end and attaches to short filaments of F-actin (blue) at the other end, aided by protein 4.1 (orange). Up to six spectrins can bind to one actin filament, making the skeleton a hexagonal array. The membrane skeleton is attached to band 3 (pink), the anion exchanger, via ankyrin near the spectrin self-association site, and to band 3 via proteins 4.1 and 4.2 (yellow) at the actin end of spectrin. Other proteins (gray) participate in large protein complexes at each of these sites. Defects in the "vertical" connections between the membrane skeleton and band 3 result in hereditary spherocytosis. Defects in the "horizontal" interactions that hold the membrane skeleton together cause hereditary elliptocytosis or its severe variant, hereditary pyropoikilocytosis.(Modified with permission from ...

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