Targeted disruption of the beta adducin gene (Add2) causes red blood cell spherocytosis in mice

Adducins are a family of cytoskeleton proteins encoded by three genes (alph a, beta, gamma), In a comprehensive assay of gene expression, we show the u biquitous expression of alpha- and gamma-adducins in contrast to the restri cted expression of beta-adducin, beta-adducin is expressed at high levels i n brain and hematopoietic tissues (bone marrow in humans, spleen in mice). To elucidate adducin's role in vivo, we created beta-adducin null mice by g ene targeting, deleting exons 9-13, A 55-kDa chimeric polypeptide is produc ed from the first eight exons of beta-adducin and part of the neo cassette in spleen but is not detected in peripheral RBCs or brain. beta-adducin nul l RBCs are osmotically fragile, spherocytic, and dehydrated compared with t he wild type, resembling RBCs from patients with hereditary spherocytosis, The lack of beta-adducin in RBCs leads to decreased membrane incorporation of alpha-adducin (30% of normal) and unexpectedly promotes a 5-fold increas e in gamma-adducin incorporation into the RBC membrane skeleton. This study demonstrates adducin's importance to RBC membrane stability in vivo.