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Novel roles for erythroid Ankyrin-1 revealed through an ENU-induced null mouse mutant

journal contribution
posted on 2023-05-17, 01:11 authored by Rank, G, Sutton, R, Marshall, V, Lundie, RJ, Caddy, J, Romeo, T, Fernandez, K, McCormack, MP, Cooke, BM, Simon James FooteSimon James Foote, Crabb, BS, Curtis, DJ, Hilton, DJ, Kile, BT, Jane, SM
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 anemic in utero and most die perinatally, indicating that Ank-1 plays a nonredundant role in erythroid development. The surviving pups exhibit features of severe hereditary spherocytosis (HS), with marked hemolysis, jaundice, compensatory extramedullary erythropoiesis, and tissue iron overload. Red cell membrane analysis reveals a complete loss of ANK-1 protein and a marked reduction in B- spectrin. As a consequence, the red cells exhibit total disruption of cytoskeletal architecture and severely altered hemorheologic properties. Heterozygous mutant mice, which have wild-type levels of ANK-1 and spectrin in their RBC membranes and normal red cell survival and ultrastructure, exhibit profound resistance 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 resistance.

History

Publication title

Blood

Volume

113

Issue

14

Pagination

3352-3362

ISSN

0006-4971

Department/School

Menzies Institute for Medical Research

Publisher

Amer Soc Hematology

Place of publication

1900 M Street. Nw Suite 200, Washington, USA, Dc, 20036

Repository Status

  • Restricted

Socio-economic Objectives

Diagnosis of human diseases and conditions

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