Faculty Collaboration Database

Mutations in the murine erythroid alpha-spectrin gene alter spectrin mRNA and protein levels and spectrin incorporation into the red blood cell membrane skeleton. Blood 2003 Jan 01;101(1):325-30

Date

10/24/2002

Pubmed ID

12393645

DOI

10.1182/blood-2002-01-0113

Scopus ID

2-s2.0-0037218053 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

Tetramers of alpha- and beta-spectrin heterodimers, linked by intermediary proteins to transmembrane proteins, stabilize the red blood cell cytoskeleton. Deficiencies of either alpha- or beta-spectrin can result in severe hereditary spherocytosis (HS) or hereditary elliptocytosis (HE) in mice and humans. Four mouse mutations, sph, sph(Dem), sph(2BC), and sph(J), affect the erythroid alpha-spectrin gene, Spna1, on chromosome 1 and cause severe HS and HE. Here we describe the molecular alterations in alpha-spectrin and their consequences in sph(2BC)/sph(2BC) and sph(J)/sph(J) erythrocytes. A splicing mutation, sph(2BC) initiates the skipping of exon 41 and premature protein termination before the site required for dimerization of alpha-spectrin with beta-spectrin. A nonsense mutation in exon 52, sph(J) eliminates the COOH-terminal 13 amino acids. Both defects result in instability of the red cell membrane and loss of membrane surface area. In sph(2BC)/sph(2BC), barely perceptible levels of messenger RNA and consequent decreased synthesis of alpha-spectrin protein are primarily responsible for the resultant hemolysis. By contrast, sph(J)/sph(J) mice synthesize the truncated alpha-spectrin in which the 13-terminal amino acids are deleted at higher levels than normal, but they cannot retain this mutant protein in the cytoskeleton. The sph(J) deletion is near the 4.1/actin-binding region at the junctional complex providing new evidence that this 13-amino acid segment at the COOH-terminus of alpha-spectrin is crucial to the stability of the junctional complex.

Author List

Wandersee NJ, Birkenmeier CS, Bodine DM, Mohandas N, Barker JE

MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Binding Sites
Erythrocyte Deformability
Erythrocyte Membrane
Erythrocytes
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Molecular Sequence Data
Mutation
Protein Binding
RNA, Messenger
Reticulocytes
Spectrin