Molecular determinants of clinical expression of hereditary elliptocytosis and pyropoikilocytosis

Abstract

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 alpha spectrin mutants characterized by a spectrin dimer (SpD) self-association defect related to a structural abnormality of the alpha I domain of spectrin. Twenty-nine subjects had common HE, 13 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) spectrin heterodimer self-association, as manifested by the percentage of SpD in the 4 degrees 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. Our analysis indicates that the severity of hemolysis may be correlated with quantitative differences in the percentage of SpD in the 4 degrees C spectrin extract, as well as the total spectrin content of the membrane. Thus, HPP subjects, who have the most severe hemolytic anemia, have the highest percentage of SpD as well as a decreased spectrin content. HE subjects and asymptomatic carriers, respectively, have a lower percentage of SpD and a normal spectrin content. Factors influencing these two determinants include functional differences between the individual spectrin mutants, the relative amounts of mutant spectrin present in the cells, the stability of mutant spectrin, and the possibility of a superimposed genetic defect involving spectrin synthesis.

Amino-acid substitution in α-spectrin commonly coinherited with nondominant hereditary spherocytosis

“…A number of genetic disorders of the ␣-spectrin gene have been described that are associated with decreased synthesis or accumulation of ␣-spectrin chains. Some patients with the syndrome of hereditary pyropoikilocytosis (HPP) [1][2][3][4]32] are doubly heterozygous for two different types of mutant ␣-spectrin genes: an ␣-spectrin gene encoding a structural ␣-chain variant associated with hereditary elliptocytosis (HE), and a second gene associated with markedly decreased accumulation of ␣-spectrin chains and concomitant marked deficiency of ␣-spectrin mRNA [33,34]. Two infants with hydrops fetalis due to severe nonimmune hemolytic anemia were born in a family in which one parent had apparently typical dominant HS and the other parent was hematologically normal [35].…”