RED CELLS, IRON, AND ERYTHROPOIESIS

Insights into the role of ankyrin-1 (ANK-1) in the formation and stabilization of the red cell cytoskeleton have come from studies on the nb/nb mice, which carry hypomorphic alleles of Ank-1. Here, we revise several paradigms established in the nb/nb mice through analysis of an N-ethyl-N-nitrosourea (ENU)–induced Ank-1–null mouse. Mice homozygous for the Ank-1 mutation are profoundly ane-mic in utero and most die perinatally, indicating that Ank-1 plays a nonredun-dant role in erythroid development. The surviving pups exhibit features of severe hereditary spherocytosis (HS), with marked hemolysis, jaundice, compensa-tory extramedullary erythropoiesis, and tissue iron overload. Red cell membrane analysis reveals a complete loss of ANK-1 protein and a marked reduction in -spectrin. As a consequence, the red cells exhibit total disruption of cytoskeletal architecture and severely altered hemo-rheologic properties. Heterozygous mu-tant mice, which have wild-type levels of ANK-1 and spectrin in their RBC mem-branes and normal red cell survival and ultrastructure, exhibit profound resis-tance to malaria, which is not due to impaired parasite entry into RBC. These findings provide novel insights into the role of Ank-1, and define an ideal model for the study of HS and malarial resis-tance. (Blood. 2009;113:3352-3362