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Molecular basis of spectrin and ankyrin deficiencies in severe hereditary
spherocytosis: evidence implicating a primary defect of ankyrin
M Hanspal, SH Yoon, H Yu, JS Hanspal, S Lambert, J Palek and JT Prchal
Department of Biomedical Research, St. Elizabeth's Hospital of Boston, MA
02135.
While varying degrees of spectrin deficiency have been found in the
majority of patients with hereditary spherocytosis (HS), a combined severe
deficiency of both spectrin and the spectrin-binding protein, ankyrin, has
been reported only in two patients with severe HS. To elucidate the
molecular basis of these protein deficiencies, we have studied the
synthesis, assembly, and the mRNA levels of spectrin and ankyrin in
peripheral blood reticulocytes in one of the previously reported probands.
Pulse-labeling studies showed that in HS reticulocytes, the synthesis of
alpha-spectrin was comparable with control reticulocytes while that of
beta-spectrin was increased about fourfold, presumably reflecting increased
erythropoietic drive. On the HS reticulocyte membrane, the amount of newly
assembled spectrin was reduced to about half of the control values,
presumably reflecting a decrease in the synthesis of the spectrin binding
protein, ankyrin: the ankyrin synthesis was nearly absent in the cytosol
and the amounts of membrane-associated ankyrin were reduced to about half
of the normal values. The changes in the amounts of spectrin and ankyrin
mRNAs quantitated by slot blot and Northern blot analyses were comparable
with changes in the synthesis of these proteins: The alpha spectrin mRNA
was within a control range and the beta-spectrin mRNA was slightly
increased, while the amounts of ankyrin mRNA were reduced to about 50% of
control values. We conclude that the primary defect underlying the combined
spectrin and ankyrin deficiency is a deficiency of ankyrin mRNA leading to
a reduced synthesis of ankyrin which, in turn, underlies the decreased
assembly of spectrin on the membrane.
Volume 77,
Issue 1,
pp. 165-173,
01/01/1991
Copyright © 1991 by The American Society of Hematology
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