Red-Cell-Membrane Polypeptide Aggregates in Glucose-6-Phosphate Dehydrogenase Mutants with Chronic Hemolytic Disease: A Clue to the Mechanism of Hemolysis

Red-cell membranes from patients with glucose-6-phosphate dehydrogenase deficiency were studied with polyacrylamide gel electrophoresis and gel filtration chromatography in sodium dodecyl sulfate. Membranes from each of five such patients who also had chronic hemolytic disease contained polypeptide aggregates within two molecular-weight ranges (4.4 X 10⁵ and >50 X 10⁶ daltons). The 4.4 X 10⁵ dalton aggregates were not detectable in red-cell membranes of patients with the enzyme deficiency without chronic hemolysis or in membranes from normal subjects, and the >50 X 10⁶ dalton aggregates were not found in appreciable amounts in these cells. The aggregates were dissociated by mercaptoethanol or dithiothreitol — indicating that they were formed by intermolecular disulfide bonds. The polypeptide aggregates contained spectrin but not globin. Red-cell deformability was decreased in aggregate-containing cells. We postulate that the polypeptide aggregates are indicators of oxidant damage to the red-cell membrane, which results in decreased deformability and chronic hemolysis. (N Engl J Med 301:522–527, 1979) GLUCOSE-6-phosphate dehydrogenase deficiency, an inherited lack of the red-cell enzyme, results from any of a large number of structural-gene mutations.¹ The common glucose-6-phosphate dehydrogenase mutants, A- and Mediterranean, are characterized clinically by hemolysis that is almost always intermittent and associated with infections or drug administration. Other, much less frequently encountered mutations result in nonspherocytic, chronic hemolytic disease,^{2 3 4} but the mechanism responsible for its occurrence is unknown.¹ Although several theories have been proposed to explain why some patients with glucose-6-phosphate dehydrogenase deficiency have chronic hemolysis,⁵ none appear to explain the diversity found in this group of patients.^{5 6 7 8} We have recently described.