Indirect evidence suggests that the genetic defect in hereditary spherocytosis lies in the erythrocyte membrane skeleton, a submembranous meshwork of proteins (principally spectrin, actin, and protein 4.1) responsible for membrane shape and structural stability.
Some patients with recessive HS have a mutation in the spectrin alpha-2 domain (S.L.M. et al., unpublished observations), and a few dominant HS patients have an unstable beta-spectrin that is easily oxidized, which damages the protein 4.1 binding site and weakens spectrin-actin interactions.
The defective spectrin-protein-4.1 interaction in these kindreds (referred to as type I HS) leads to a weakened spectrin-protein-4.1-actin ternary complex, which in turn may lead to the friable membrane skeleton and suggested membrane instability related to this disorder.
The identical substitution has been recently identified in an analogous amino-acid position within the actin binding domain of beta-spectrin leading to hereditary spherocytosis.
Thus, a primary structural defect in the beta subunit of spectrin in this subtype of HS may lead to oxidant sensitivity, and secondarily, to a functional defect in the binding of spectrin to protein 4.1 and actin.