Abnormal spectrin in hereditary elliptocytosis
SL Marchesi, WJ Knowles, JS Morrow, M Bologna and VT Marchesi
An abnormal alpha subunit of erythrocyte spectrin has been described in
hereditary pyropoikilocytosis (HPP), a rare hemolytic anemia characterized
by erythrocyte budding and fragmentation. In HPP spectrin, the N terminal
domain of the alpha subunit (alpha I T80) shows increased susceptibility to
tryptic digestion, resulting in cleavage to a 50,000-d peptide, presumably
due to a change in primary structure of the alpha I domain which alters
conformation and generates the new cleavage site. The functional result of
this conformational alteration is marked impairment of spectrin oligomer
formation in vitro, consistent with the established role of alpha I T80 in
spectrin self-association. In the present study, we demonstrate an abnormal
spectrin alpha subunit in two kindreds with hereditary elliptocytosis (HE)
that is qualitatively identical to HPP spectrin. Clinical expression of HE
in these families ranges from mild elliptocytosis without hemolysis to
severe poikilocytic hemolytic anemia clinically resembling HPP. In all
affected individuals, a fraction of alpha I T80 is abnormal, as shown by
its cleavage during mild tryptic digestion to the 50 kd peptide described
in HPP; the fraction of alpha I T80 affected is directly proportional to
the severity of clinical expression of HE. Spectrin oligomer formation is
likewise impaired to a degree which correlates with hematologic disease.
One of the HE kindreds studied demonstrated polymorphism in the spectrin
alpha II domain, previously described as a frequent occurrence in blacks.
This family also demonstrates a variant alpha III domain in spectrin that
has not previously been described. We conclude that the abnormality in the
alpha I domain originally described in HPP spectrin is shared by a subset
of patients with HE; the severity of clinical expression, ranging from mild
nonhemolytic HE to poikilocytic hemolytic anemia, is related to the
fractional quantity of the alpha subunit that is affected.
Volume 67,
Issue 1,
pp. 141-151,
01/01/1986
Copyright © 1986 by The American Society of Hematology
