Defective spectrin dimer-dimer association with hereditary elliptocytosis.

We examined erythrocytes from 18 patients with hereditary elliptocytosis. Spectrin from eight patients (referred to as type 1) was defective in dimer-dimer association as demonstrated in two ways. First, there was an increased amount of spectrin dimer with a concomitant decrease in tetramer as measured in erythrocyte membrane preparations extracted at 0 degrees C under low-salt conditions (the amount of spectrin dimer was 15-33% of total spectrin species compared with a normal range of 3-7%). Second, the equilibrium constants of spectrin dimer-dimer association were decreased in both solution and in situ membrane. Spectrin from the remaining 10 patients (referred to as type 2) showed normal dimer-dimer association. Membrane skeletons, produced from ghosts of both types of hereditary elliptocytosis by Triton X-100 extraction, were unstable when mechanically shaken. Because spectrin tetramers, but not dimers, can crosslink actin, we postulate that the defective spectrin dimer-dimer association in type 1 diminishes actin crosslinking and thus is responsible for membrane skeletal instability. A defective protein-protein association in type 2, however, remains to be identified.