Of mice and men: the mice were right.

Editorial The human erythrocyte has provided the basis for much of our basic understanding of plasma membrane structure, beginning with elucidation of the bilayer organization of phospholipids by Gorter and Grendel, and more recently with resolution of the detailed structure of the spectrin-based membrane skeleton. The spectrin skeleton is an assembly of proteins localized on the cytoplasmic surface of the plasma membrane and is responsible for stability of erythrocytes in the high shear environment of the vascular system. The spectrin skeleton of human erythro-cytes has been resolved in terms of the major interacting proteins , their sites of recognition and domain organization, as well as their primary structure. Building on this foundation, understanding of the molecular basis for abnormal erythrocyte membranes has undergone a paradigm shift in the past decade (see Seminars in Hematology volume 30 for a series of reviews). Two papers in this issue of The Journal from the laboratories of Bemard Forget (1) and Jiri Palek (2) exemplify this revolution and present two new molecular defects in proteins of the spectrin skeleton. These papers are significant in terms of their contribution to hematology and also provide valuable insight into structure-function relationships of skeletal proteins. In a broader sense, the detailed dissection of defects in the spectrin skeleton of erythrocytes provides a model for understanding other diseases involving multiprotein structures. Gallagher and colleagues (1) describe a mutation in ,3 spec-trin which, in homozygotes, results in fetal death in the third trimester with a presentation of hydrops fetalis. Using a mutant /6-spectrin polypeptide, the authors were able to demonstrate that the mutation of spectrin results in impaired association with the a spectrin and presumably reduced levels of spectrin tetramer in erythrocytes. The lethal consequences of spectrin mutations in utero are in contrast to the general view that hereditary hemolytic anemias are relatively mild disorders with a dominant or sporadic inheritance. Of interest, the results of Gallagher et al. (1) were foreshadowed by studies with anemic mice discovered by Bermstein and his colleagues at the Jackson Laboratories. Four strains of mice have been characterized with recessively inherited mutations resulting in severe, life-threatening anemia and abnormally shaped erythrocytes. Erythrocytes from the mutant mice exhibit deficiency of spectrin as a common feature, and the extent of spectrin deficiency correlates with severity of the anemia (3, 4). The possibility that the severe anemias in mice were related to hereditary spherocytosis and elliptocytosis in …