Defective spectrin integrity and neonatal thrombosis in the first mouse model for severe hereditary elliptocytosis

Mutations affecting the conversion of spectrin dimers to tetramers result i n hereditary elliptocytosis (HE), whereas a deficiency of human erythroid a lpha- or beta -spectrin results in hereditary spherocytosis (HS), All spont aneous mutant mice with cytoskeletal deficiencies of spectrin reported to d ate have HS, Here, the first spontaneous mouse mutant, sph(Dem)/sph(Dem), W ith Severe HE is described. The sph(Dem) mutation is the insertion of an in tracisternal A particle element in intron in of the erythroid alpha -spectr in gene. This causes exon skipping, the in-frame deletion of 46 amino acids from repeat 5 of alpha -spectrin and alters spectrin dimer/tetramer stabil ity and osmotic fragility. The disease is more severe in sphDem/sphDem neon ates than in alpha -spectrin-deficient mice with HS, Thrombosis and infarct ion are not, as in the HS mice, limited to adults but occur soon after birt h. Genetic background differences that exist between HE and HS mice are sus pect, along with red blood cell morphology differences, as modifiers of thr ombosis timing. sph(Dem)/sph(Dem) mice provide a unique model for analyzing spectrin dimer-to-tetramer conversion and identifying factors that influen ce thrombosis. (C) 2001 by The American Society of Hematology.