title: Deficiency of alpha-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis.
abstract: 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 alpha-spectrin synthesis and a markedly reduced amount of alpha- and beta-spectrin on cell membranes. No alpha-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 alpha-spectrin synthesis is proposed as the cause of the lethal anemia, resulting in cell fragmentation during precursor enucleation or during egress from bone marrow.
authors.affiliation: Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey 17033.
authors.forename: C F
authors.initials: CF
authors.lastname: Whitfield
authors.forename: J B
authors.initials: JB
authors.lastname: Follweiler
authors.forename: L
authors.initials: L
authors.lastname: Lopresti-Morrow
authors.forename: B A
authors.initials: BA
authors.lastname: Miller
mesh_terms: D001457:Anion Exchange Protein 1, Erythrocyte / Q000096:biosynthesis; D015153:Blotting, Western; D002478:Cells, Cultured; D015672:Erythroid Precursor Cells / Q000378:metabolism*; D005804:Genes, Lethal; D006801:Humans; D009996:Osmotic Fragility; D011233:Precipitin Tests; D013049:Spectrin / Q000096:biosynthesis*; D013103:Spherocytosis, Hereditary / Q000235:genetics / Q000378:metabolism*
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D013049:Spectrin