Faculty Research 1990 - 1999

Title

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

Document Type

Article

Publication Date

1999

Keywords

Animal, Blotting-Northern, Calmodulin-Binding-Proteins, Erythrocytes, Erythroid-Progenitor-Cells, Exons, Mice, Mice-Inbred-C57BL, Mice-Knockout, Models-Genetic, Mutagenesis, Osmolar-Concentration, Osmotic-Fragility, Poly-A, RNA, Spherocytosis-Hereditary, Spleen, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Tissue-Distribution

JAX Source

Proc Natl Acad Sci USA 1999 Sep; 96(19):10717-22.

Grant

DK02070/DK/NIDDK, HL55321/HL/NHLBI, DK26263/DK/NIDDK

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.

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