Mutation of a highly conserved residue of βI spectrin associated with fatal and near-fatal neonatal hemolytic anemia

Abstract

We studied an infant with severe nonimmune hemolytic anemia and hydrops fetalis at birth. His neonatal course was marked by ongoing hemolysis of undetermined etiology requiring repeated erythrocyte transfusions. He has remained transfusion-dependent for more than 2 yr. A previous sibling born with hemolytic anemia and hydrops fetalis died on the second day of life. Peripheral blood smears from the parents revealed rare elliptocytes. Examination of their erythrocyte membranes revealed abnormal mechanical stability as well as structural and functional abnormalities in spectrin. Genetic studies revealed that the proband and his deceased sister were homozygous for a mutation of βIΣ1 spectrin, L2025R, in a region of spectrin that is critical for normal function. The importance of leucine in this position of the proposed triple helical model of spectrin repeats is highlighted by its evolutionary conservation in all β spectrins from Drosophila to humans. Molecular modeling demonstrated the disruption of hydrophobic interactions in the interior of the triple helix critical for spectrin function caused by the replacement of the hydrophobic, uncharged leucine by a hydrophilic, positively charged arginine. This mutation must also be expressed in the βIΣ2 spectrin found in muscle, yet pathologic and immunohistochemical examination of skeletal muscle from the deceased sibling was unremarkable.