Mild spherocytic hereditary elliptocytosis and altered levels of alpha- and gamma-adducins in beta-adducin-deficient mice

The membrane skeleton, a dynamic network of proteins associated with the pl asma membrane, determines the shape and mechanical properties of erythrocyt es. Deficiencies or defects in membrane skeletal proteins are associated wi th inherited disorders of erythrocyte morphology and function. Adducin is o ne of the proteins localized at the spectrin-actin junction of the membrane skeleton. In this work we show that deficiency of beta-adducin produces an 80% decrease of or-adducin and a fourfold up-regulation of gamma-adducin i n erythrocytes. beta-Adducin or any other isoform generated by translation of abnormally spliced messenger RNAs could not be detected by our antibodie s either in ghosts or in cytoplasm of -/- erythrocytes, Actin levels were d iminished in mutant mice, suggesting alterations in the actin-spectrin junc tional complexes due to the absence of adducin, Elliptocytes, ovalocytes, a nd occasionally spherocytes were found in the blood film of -/- mice. Hemat ological values showed an increase in reticulocyte counts and mean corpuscu lar hemoglobin concentration, decreased mean corpuscular volume and hematoc rit, and normal erythrocyte counts that, associated to splenomegaly, indica te that the mice suffer from mild anemia with compensated hemolysis. These modifications are due to a loss of membrane surface and dehydration that re sult in an increase in the osmotic fragility of red blood cells. The marked alteration in osmotic fragility together with the predominant presence of elliptocytes is reminiscent of the human disorder called spherocytic heredi tary elliptocytosis. Our results suggest that the amount of adducin remaini ng in the mutant animals (presumably alpha gamma adducin) could be function al and might account for the mild phenotype. (C) 2000 by The American Socie ty of Hematology.