Deficiency of α-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis

A child diagnosed in utero with hydrops fetalis and a hematocrit of 6.4% was studied to determine the etiology of the anemia. Fetal red blood cells (RBCs) obtained during in utero transfusion had extremely abnormal osmotic fragility. A maternal history of mild autosomal dominant hereditary spherocytosis was present, and the father, who was hematologically normal, had a slightly abnormal osmotic fragility test. The patient was transfusion dependent after birth, with circulating nucleated RBCs but less than 1% reticulocytes. The patient's anemia failed to respond to splenectomy. Because mature RBCs of the patient were not available for study, progenitor-derived erythroblasts grown in culture were investigated. Immunodot assays of the patient's progenitor-derived cells showed a total cell spectrin content 26% of normal. Immunoprecipitation of whole burst-forming units-erythroid-derived cells and solubilized membranes from cells pulse-labeled with ³⁵S-methionine showed a severe deficiency in α-spectrin synthesis and a markedly reduced amount of α- and β-spectrin on cell membranes. No α-spectrin degradation products were found within the cells or were produced during membrane preparation. Ankyrin content and band 3 synthesis were not different from control. Inheritance of two genetic defects causing severely reduced α-spectrin synthesis is proposed as the cause of the lethal anemia, resulting in cell fragmentation during precursor enucleation or during egress from bone marrow.