Molecular Determinants of Clinical Expression

The clinical severity of common hereditary elliptocytosis (HE) is highly variable. ranging from an asymptomatic carrier state to a severe hemolytic anemia. To elucidate the molecular basis of this variable clinical expression. we evaluated 56 subjects from 24 HE kindred. who carry a spectrin mutants characterized by a spectrin dimer (SpD) self-association defect related to a structural abnormality of the a I domain of spectrin. Twenty-nine subjects had common HE, 1 3 subjects have a closely related disorder. hereditary pyropoikilocytosis (HPP). and 14 are asymptomatic carriers. We compared the severity of hemolysis with the following biochemical parameters: (a) spectrmn heterodimer self-association, as manifested by the percentage of SpD in the 4’C low ionic strength spectrin extract; (b) spectrin structure. as examined by limited tryptic digestion of spectrin; and (c) spectrin content of the RBC membrane.