title: Targeted disruption of the beta adducin gene (Add2) causes red blood cell spherocytosis in mice.
abstract: Adducins are a family of cytoskeleton proteins encoded by three genes (alpha, beta, gamma). In a comprehensive assay of gene expression, we show the ubiquitous expression of alpha- and gamma-adducins in contrast to the restricted expression of beta-adducin. beta-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 beta-adducin null mice by gene targeting, deleting exons 9-13. A 55-kDa chimeric polypeptide is produced 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 null RBCs are osmotically fragile, spherocytic, and dehydrated compared with the 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 increase in gamma-adducin incorporation into the RBC membrane skeleton. This study demonstrates adducin's importance to RBC membrane stability in vivo.
authors.affiliation: Department of Internal Medicine (Hematology), Yale University School of Medicine, New Haven, CT 06510, USA. Diana.Gilligan@yale.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Gilligan
authors.forename: L
authors.initials: L
authors.lastname: Lozovatsky
authors.forename: B
authors.initials: B
authors.lastname: Gwynn
authors.forename: C
authors.initials: C
authors.lastname: Brugnara
authors.forename: N
authors.initials: N
authors.lastname: Mohandas
authors.forename: L L
authors.initials: LL
authors.lastname: Peters
mesh_terms: D000740:Anemia / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D004912:Erythrocytes / Q000166:cytology*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005091:Exons; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D016296:Mutagenesis; D009994:Osmolar Concentration; D009996:Osmotic Fragility / Q000235:genetics; D011061:Poly A / Q000032:analysis; D012313:RNA / Q000032:analysis; D013103:Spherocytosis, Hereditary / Q000235:genetics; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; D011061:Poly A; D012313:RNA; D000099291:Adducins