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 (α, β, γ). In a comprehensive assay of gene expression, we show the ubiquitous expression of α- and γ-adducins in contrast to the restricted expression of β-adducin. β-adducin is expressed at high levels in brain and hematopoietic tissues (bone marrow in humans, spleen in mice). To elucidate adducin’s role in vivo, we created β-adducin null mice by gene targeting, deleting exons 9–13. A 55-kDa chimeric polypeptide is produced from the first eight exons of β-adducin and part of the neo cassette in spleen but is not detected in peripheral RBCs or brain. β-adducin null RBCs are osmotically fragile, spherocytic, and dehydrated compared with the wild type, resembling RBCs from patients with hereditary spherocytosis. The lack of β-adducin in RBCs leads to decreased membrane incorporation of α-adducin (30% of normal) and unexpectedly promotes a 5-fold increase in γ-adducin incorporation into the RBC membrane skeleton. This study demonstrates adducin’s importance to RBC membrane stability in vivo.