Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in alpha-spectrin-deficient red cells.
Document Type
Article
Publication Date
2010
Keywords
Alternative-Splicing, Amino-Acid-Sequence, Animals, Anion-Exchange-Protein-1-Erythrocyte, Base-Sequence, Calmodulin-Binding-Proteins, Codon-Nonsense, DNA-Primers, Erythrocyte-Membrane, Erythrocytes-Abnormal, Mice-Inbred-C57BL, Mice-Inbred-NOD, Mice-Mutant-Strains, Molecular-Sequence-Data, Mutation, Mutation-Missense, RNA-Stability, Sequence-Homology-Amino-Acid, Spectrin, Spherocytosis-Hereditary
First Page
1804
Last Page
1814
JAX Source
Blood 2010 Mar; 115(9):1804-14.
Abstract
Five spontaneous, allelic mutations in the alpha-spectrin gene, Spna1, have been identified in mice (spherocytosis [sph], sph(1J), sph(2J), sph(2BC), sph(Dem)). All cause severe hemolytic anemia. Here, analysis of 3 new alleles reveals previously unknown consequences of red blood cell (RBC) spectrin deficiency. In sph(3J), a missense mutation (H2012Y) in repeat 19 introduces a cryptic splice site resulting in premature termination of translation. In sph(Ihj), a premature stop codon occurs (Q1853Stop) in repeat 18. Both mutations result in markedly reduced RBC membrane spectrin content, decreased band 3, and absent beta-adducin. Reevaluation of available, previously described sph alleles reveals band 3 and adducin deficiency as well. In sph(4J), a missense mutation occurs in the C-terminal EF hand domain (C2384Y). Notably, an equally severe hemolytic anemia occurs despite minimally decreased membrane spectrin with normal band 3 levels and present, although reduced, beta-adducin. The severity of anemia in sph(4J) indicates that the highly conserved cysteine residue at the C-terminus of alpha-spectrin participates in interactions critical to membrane stability. The data reinforce the notion that a membrane bridge in addition to the classic protein 4.1-p55-glycophorin C linkage exists at the RBC junctional complex that involves interactions between spectrin, adducin, and band 3.
Recommended Citation
Robledo RF,
Lambert AJ,
Birkenmeier CS,
Cirlan MV,
Cirlan AF,
Campagna DR,
Lux SE,
Peters LL.
Analysis of novel sph (spherocytosis) alleles in mice reveals allele-specific loss of band 3 and adducin in alpha-spectrin-deficient red cells. Blood 2010 Mar; 115(9):1804-14.