Chapter 183

## Abstract

Abstract

1. 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.

2. 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.

3. 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.

4. 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 mechanically rigid, osmotically fragile, and selectively retained in the spleen and destroyed. Patients with the common, autosomal dominant form of HS typically have mild to moderate anemia, modest splenomegaly, and intermittent jaundice. Individuals with compensated hemolysis and no anemia are common, and occasionally severe, transfusion-dependent anemia occurs. Other complications associated with HS include neonatal jaundice, gallbladder disease, and aplastic crises. Approximately 25 percent of HS cases occur sporadically, about half of which are cases with de novo mutations and the other half, a recessive form of HS. Patients with severe HS respond well to splenectomy clinically, but the underlying red cell abnormalities persist.

5. Red blood cells from most HS patients are deficient in spectrin and ankyrin. In these patients clinical severity and response to splenectomy correlate well with the degree of spectrin deficiency. Red cell osmotic fragility is also proportional to spectrin content. In most cases the spectrin deficiency is secondary to ankyrin loss, because primary defects in ankyrin are the major cause of HS in Europeans and Americans (≈50 percent of cases), but mutations in the β-spectrin gene are also fairly common (≈25 percent). In both cases most of the mutations are private and differ in each family. They are often null mutations that produce an unstable or truncated peptide. Variable compensation occurs by the normal allele, in trans, which may account for the variable severity of similar null mutations. Mutations in α-spectrin are rare (≈5 percent), but they cause some of the more severe, recessive forms of HS and the most severe degrees of spectrin deficiency. About 30 percent of HS patients have normal red cell spectrin content. Most have combined band 3 and protein 4.2 deficiency due to dominant mutations in the band 3 gene (≈20 percent). The remainder have isolated 4.2 deficiency due to recessive mutations in the protein 4.2 gene. This is an uncommon mutation in western countries (≈5 percent) but is common, as is band 3 deficiency, in Japan.

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