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PMID: 1975598 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Point mutation in the beta-spectrin gene associated with alpha I/74 hereditary elliptocytosis. Implications for the mechanism of spectrin dimer self-association.

The Journal of clinical investigation ·Vol. 86 ·No. 3 ·1990-09-00 ·Pages 909-16

Tse WT, Lecomte MC, Costa FF, Garbarz M, Feo C, Boivin P, Dhermy D, Forget BG

Abstract

alpha I/74 hereditary elliptocytosis (HE) is a subgroup of HE in which patients exhibit an impaired self-association of spectrin dimers and an abnormal proteolytic cleavage of the alpha I domain of spectrin. We studied a family in which the proband presented with a severe neonatal hemolytic anemia with poikilocytosis. Biochemical analysis of erythrocytes from the proband and his family members allowed us to ascertain a diagnosis of homozygosity for alpha I/74 HE in the proband and heterozygosity in his parents and several of their offspring. Results of polymorphism linkage analysis suggested that the defect in this family was located in beta rather than alpha spectrin. We analyzed the 3' end of the beta-spectrin gene of the proband and detected a mutation that changes a codon for alanine to one for proline. Allele-specific oligomer hybridization on slot blots of DNA from other family members confirmed the presence of the mutation only in members heterozygous for the disorder. This is the first example of a point mutation in the beta-spectrin chain that is associated with defective spectrin dimer self-association and an abnormal proteolytic cleavage of the alpha chain. Based on this finding, we propose a model for the mechanism of interaction between the alpha- and beta-spectrin chains.

MeSH Terms
Amino Acid Sequence Base Sequence Electrophoresis, Gel, Two-Dimensional Elliptocytosis, Hereditary/genetics Genetic Linkage Humans Macromolecular Substances Molecular Sequence Data Mutation Oligonucleotides Pedigree Polymerase Chain Reaction Polymorphism, Restriction Fragment Length Protein Conformation Restriction Mapping Spectrin/genetics,ultrastructure
Chemicals
Macromolecular Substances Oligonucleotides Spectrin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tse W T
Department of Human Genetics, Yale University School of Medicine, New Haven, Connecticut 06510.
Lecomte M C
Costa F F
Garbarz M
Feo C
Boivin P
Dhermy D
Forget B G
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI114792
Published
1990-09-00
Pages
909-16
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC296810
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI114792 PMC Full Text View journal details
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