Spectrin abnormalities

Abnormalities in the Amount or Structure of Spectrin Cause Hereditary Spherocytosis Elliptocytosis... 

One cause of hereditary spherocytosis (Figure 52-5) is a deficiency in the amount of spectrin or abnormalities of its structure, so that it no longer tightly binds the other proteins with which it normally interacts. This weakens the membrane and leads to the spherocytic shape. Abnormalities of ankyrin and of bands 3 and 4.1 are involved in other cases. 

Hereditary elliptocytosis is a genetic disorder that is similar to hereditary spherocytosis except that affected red blood cells assume an elliptic, disk-hke shape, recognizable by microscopy. It is also due to abnormalities in spectrin some cases reflect abnormahties of band 4.1 or of glycophorin C. 

Causes within the membrane include abnormahties of proteins. The most important conditions are hereditary spherocytosis and hereditary eUiptocytosis, principally caused by abnormalities in the amount or structure of spectrin (see above). 

What is the function of the membrane skeleton There is a group of hereditary diseases including spherocytosis in which erythrocytes do not maintain their biconcave disc shape but become spherical or have other abnormal shapes and are extremely fragile.269 272 Causes of spherocytosis include defective formation of spectrin tetramers and defective association of spectrin with ankyrin or the band 4.1 protein.265 273 Thus, the principal functions of these proteins in erythrocytes may be to strengthen the membrane and to preserve the characteristic shape of erythrocytes during their 120-day lifetime in the bloodstream. In other cells the spectrins are able to interact with microtubules, which are absent from erythrocytes, and to microtubule-associated proteins of the cytoskeleton (Chapter 7, Section F).270 In nerve terminals a protein similar to erythrocyte protein 4.1 may be involved in transmitter release.274 The cytoskeleton is also actively involved in transmembrane signaling. 

Spectrin forms an integral part of the erythrocyte cytoskeletal architecture any defects that disrupt the association of the spectrin heterotetra-mer or the interaction with any of the other submembranous proteins can result in RBC defects (reviewed in Hassoun and Palek, 1996). Indeed, abnormalities of the /3-spectrin N-terminus and the a-spectrin G-terminus affect the self-association site and result in hereditary elliptocytosis and hereditary pyropoikilocytosis (Delaunay, 1995 Delaunay and Dhermy, 1993 Palek and Jarolim, 1993). 

Spectrin forms the meshwork that provides red blood cells their shape. Its importance in the erythrocyte is demonstrated through spectrin mutations leading to hereditary elliptocytosis and hereditary spherocytosis. Hereditary elliptocytosis is an inherited blood disorder in which an abnormally large nnmber of erythrocytes are elliptical rather than the typical biconcave disc shape. 

The concentration of crosslinked red blood cell spectrin has been suggested as a marker of nerve protein crosslinking damage that leads to slower conduction velocities and abnormal nerves due to protein adduct formation initially with dithiocarbamates which decompose to form isothiocyanate adducts (Valentine et al. 1993). These latter adducts can then cause the actual crosslinking of both spectrin and nerve protein. 

Spiro Site s red blood cells are deficient in spectrin. This deficiency impairs ) the ability of his erythrocytes to maintain the redundant surface area neces- sary to maintain deformability. Mechanical stresses in the circulation cause progressive loss of pieces of membrane. As membrane components are lost, Spiro Site s red blood cells become spherical and unable to deform. Elis spleen is enlarged because of the large number of red blood cells that have become trapped within it. His erythrocytes are lysed by mechanical stresses in the circulation and by macrophages in the spleen. Consequently, this hemolytic process results in an anemia. His gallstones were the result of the large amounts of bilirubin that were produced and stored in the gallbladder as a result of the hemolysis. The abnormally rounded red cells seen on a blood smear are characteristic of hereditary spherocytosis. 

An abnormal blood group S-s active sialoglycoprotein has been detected in the membrane of Miltenberger class III, IV, and V human erythrocytes. Interactions among the major sialoglycoproteins and peripheral proteins of human erythrocytes have been studied by fluorescence energy transfer. Divalent cations are necessary for the direct association between membrane sialoglycoproteins and spectrin. 

Some hemolytic anemias arise from abnormalities in the protein skeleton of the E.m. One form of Hereditary spherocytosis (fragile, inflexible, spherical erythrocytes) is due to decreased synthesis of normal spectrin and the presence of an abnormal spectrin that binds band 4.1 protein with decreased affinity another form is due to the absence of band 4.1 pro-... 

Possible abnormal linkage between red cell membrane glycophorin and spectrin... 

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