Combined deletion of mouse dematin-headpiece and ß-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic Anemia

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Publication Type Journal Article
School or College College of Engineering
Department Materials Science & Engineering
Creator Ostafin, Agnes
Other Author Chen, Huiqing; Khan, Anwar A.; Liu, Fei; Gilligan, Diana M.; Peters, Luanne L.; Messick, Joanne; Haschek-Hock, Wanda M.; Li, Xuerong; Chishti, Athar H.
Title Combined deletion of mouse dematin-headpiece and ß-adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic Anemia
Date 2007
Description Dematin and adducin are actin-binding proteins of the erythrocyte "junctional complex." Individually, they exert modest effects on erythrocyte shape and membrane stability, and their homologues are expressed widely in non-erythroid cells. Here we report generation and characterization of double knock-out mice lacking β-adducin and the headpiece domain of dematin. The combined mutations result in altered erythrocyte morphology, increased membrane instability, and severe hemolysis. Peripheral blood analysis shows evidence of severe hemolytic anemia with reduced number of erythrocytes/hematocrit/hemoglobin and an ~12-fold increase in the number of circulating reticulocytes. The presence of a variety of misshapen and fragmented erythrocytes correlates with increased osmotic fragility and reduced in vivo life span. Despite the apparently normal protein composition of the mutant erythrocyte membrane, the retention of the spectrin-actin complex in the membrane under low ionic strength conditions is significantly reduced by the double mutation. Atomic force microscopy reveals an increase in grain size and a decrease in filament number of the mutant membrane cytoskeleton, although the volume parameter is similar to wild type erythrocytes. Aggregated, disassembled, and irregular features are visualized in the mutant membrane, consistent with the presence of large protein aggregates. Importantly, purified dematin binds to the stripped inside-out vesicles in a saturable manner, and dematin-membrane binding is abolished upon pretreatment of membrane vesicles with trypsin. Together, these results reveal an essential role of dematin and adducin in the maintenance of erythrocyte shape and membrane stability, and they suggest that the dematin-membrane interaction could link the junctional complex to the plasma membrane in erythroid cells.
Type Text
Publisher American Society for Biochemistry and Molecular Biology (ASBMB)
Volume 282
Issue 6
First Page 4124
Last Page 4135
Language eng
Bibliographic Citation Chen, H., Khan, A. A., Liu, F., Gilligan, D. M., Peters, L. L., Messick, J., Haschek-Hock, W. M., Li, X., Ostafin, A. E., & Chishti, A. H. (2007). Combined deletion of mouse dematin-headpiece and ß -adducin exerts a novel effect on the spectrin-actin junctions leading to erythrocyte fragility and hemolytic Anemia. Journal of Biological Chemistry, 282(6), 4124-35.
Rights Management (c)American Society for Biochemistry and Molecular Biology (ASBMB) http://www.asbmb.org/
Format Medium application/pdf
Format Extent 717,561 bytes
Identifier ir-main,15420
ARK ark:/87278/s6rf6c6b
Setname ir_uspace
Date Created 2012-06-13
Date Modified 2021-05-06
ID 703402
Reference URL https://collections.lib.utah.edu/ark:/87278/s6rf6c6b
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