title: Mouse beta thalassemia, a model for the membrane defects of erythrocytes in the human disease.
abstract: The present study describes the pathophysiology, at the cellular level, of the mouse beta thalassemia and shows the pertinence of this model for the human disease. The homozygous state of mouse beta thalassemia is characterized by a clinical syndrome similar to the human beta thalassemia intermedia, but it cannot be explained by the small deficiency in beta chain synthesis. The small pool of unpaired and soluble alpha chains present in mouse reticulocytes contrasts with the large amount of insoluble alpha chains in erythrocytes which is induced by the high instability of mouse alpha chains and the absence of significant proteolysis. The amount of insoluble alpha chains associated with red cell ghosts is similar in human and mouse disease of similar severity. The study of membrane protein defects showed a decreased amount of spectrin (alpha and beta chains) and dramatic changes in the distribution of the most reactive thiol groups of membrane proteins. These results were similar to that previously described in the human disease (Rouyer-Fessard, P., Garel, M. C., Domenget, C., Guetarni, D., Bachir, D., Colonna, P., and Beuzard, Y. (1989) J. Biol. Chem. 264, 19092-19098). Abnormal density distribution curves of erythrocytes and oxidant-induced lysis of red blood cells used as functional tests were similar in the human and mouse beta thalessemia. We conclude from the present study that 1) mouse beta thalassemia is an excellent model for the membrane defects occurring in the human disease; 2) disease expression is not the reflection of the globin chain unbalance only nor of the soluble pool of alpha hemoglobin chain but mainly is a reflection of insoluble alpha chains; and 3) the rate of proteolysis and instability of alpha chains are important factors which must be taken into consideration in the pathophysiology and the clinical heterogeneity of the disease.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U. 91, Hôpital Henri Mondor, Créteil, France.
authors.forename: P
authors.initials: P
authors.lastname: Rouyer-Fessard
authors.forename: K
authors.initials: K
authors.lastname: Leroy-Viard
authors.forename: C
authors.initials: C
authors.lastname: Domenget
authors.forename: A
authors.initials: A
authors.lastname: Mrad
authors.forename: Y
authors.initials: Y
authors.lastname: Beuzard
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000302:isolation & purification; D004195:Disease Models, Animal; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism*; D006580:Genetic Carrier Screening; D006441:Hemoglobin A / Q000235:genetics / Q000302:isolation & purification*; D006461:Hemolysis; D006720:Homozygote; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D008811:Mice, Inbred DBA; D012156:Reticulocytes / Q000378:metabolism*; D013789:Thalassemia / Q000097:blood* / Q000235:genetics
chemical_list: D001798:Blood Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D006441:Hemoglobin A; D006861:Hydrogen Peroxide