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Structural and functional heterogeneity of alpha spectrin mutations
involving the spectrin heterodimer self-association site: relationships to
hematologic expression of homozygous hereditary elliptocytosis and
hereditary pyropoikilocytosis
T Coetzer, J Palek, J Lawler, SC Liu, P Jarolim, M Lahav, JT Prchal, W Wang, BP Alter and G Schewitz
Department of Biomedical Research, St Elizabeth's Hospital, Tufts
University School of Medicine, Boston, MA 02135.
Defects involving alpha spectrin (Sp) are found in patients with hereditary
elliptocytosis and a related disorder, hereditary pyropoikilocytosis (HPP).
We have previously found that the severity of hemolysis was related to the
total spectrin content of the cells and the percentage of unassembled
dimeric Sp (SpD) in the membranes, which, in turn, reflected the amount of
mutant Sp in the cell. However, no data are available comparing differences
in the function of various alpha Sp mutations to clinical severity. We now
report studies of nine homozygotes or double heterozygotes for four alpha
Sp mutations: alpha 1/74, alpha 1/46, alpha 1/65, and alpha 1/61, whose red
blood cells (RBCs) contained only the mutant Sp and no normal Sp. Sp alpha
1/74, Sp alpha 1/46, and alpha 1/65 homozygotes differed strikingly in the
severity of hemolysis that correlated with the severity of mutant Sp
dysfunction, as reflected by the fraction of unassembled SpD in the
membranes and the self-association of mutant Sp on inside-out vesicles.
Homozygotes for Sp alpha 1/74 had a very severe hemolytic anemia and their
SpD were virtually incapable of self-association, whereas SpD alpha 1/46
were not as severely affected. The Sp alpha 1/65 homozygotes had a
relatively mild hemolytic anemia and their SpD showed the least impairment
of function. Ultrastructural examination of membrane skeletons from
subjects whose SpD self-association was severely impaired showed gross
skeletal disruption and loss of hexagonal structure. In striking contrast,
the homozygote for the mildly dysfunctional Sp alpha 1/65 had only a
moderate disruption of the skeleton. Some of the homozygous or doubly
heterozygous subjects also exhibited a partial deficiency of Sp that
correlated with a RBC morphology characteristic of HPP, namely, marked
microspherocytosis with virtual absence of elliptocytes. These data
demonstrate striking differences in the function and structure of various
alpha Sp mutants that underlie differences in clinical expression.
Volume 75,
Issue 11,
pp. 2235-2244,
06/01/1990
Copyright © 1990 by The American Society of Hematology
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