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Glycoprotein IIb Leu214Pro Mutation Produces Glanzmann Thrombasthenia
With Both Quantitative and Qualitative Abnormalities in GPIIb/IIIa
Christine M. Grimaldi,
Fangping Chen,
Changhong Wu,
Harvey J. Weiss,
Barry S. Coller, and
Deborah L. French
From the Department of Medicine, Mount Sinai School of Medicine, New
York; and Columbia University College of Physicians and Surgeons, St
Luke's-Roosevelt Hospital, New York, NY.
Glanzmann thrombasthenia is an inherited bleeding disorder due to a
functional reduction or absence of platelet GPIIb/IIIa ( IIb 3) integrin receptors. Based on a
prolonged bleeding time and absence of platelet aggregation in response
to physiologic agonists, a 55-year-old white man was diagnosed as
having Glanzmann thrombasthenia. The patient's platelet fibrinogen
level was  5% of normal. As judged by complex-dependent monoclonal
antibody (MoAb) binding, surface expression of platelet GPIIb/IIIa
receptors was less than 5.5% of normal, whereas the binding of an
anti-GPIIIa specific MoAb (7H2) was 12% of normal. Immunoblot
analysis of the patient's platelet lysates showed 35% of normal
levels of GPIIIa, 30% of normal levels of GPIIb, and an abnormally
migrating fragment of GPIIb. Biotinylation of the surface proteins on
the patient's platelets followed by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis
showed only GPIIb and GPIIIa subunits of normal size. Surface
expression of platelet v3 receptors was
192% of normal, suggesting that the patient's' defect was in GPIIb.
Sequence analysis of the patient's GPIIb cDNA identified a T to C
transition at nucleotide 643, predicting a Leu214Pro substitution.
Direct sequencing of GPIIb exon 6 indicated that the patient is
homozygous for the mutation. The nature of the Leu214Pro mutation was
analyzed by expression in Chinese hamster ovary (CHO)
cells. As judged by subunit-specific MoAb binding, surface expression
of mutant receptors was 60% of normal, but these receptors were not
recognized by the complex-dependent monoclonal antibodies, 10E5 and
7E3. In addition, mutant receptors pretreated with the ligand-induced binding site MoAb AP5 were not recognized by the
activation-dependent MoAb PAC-1 and mutant expressing CHO cells did not
adhere to immobilized fibrinogen. These data suggest that the Leu214Pro
mutation in GPIIb disrupts the structural conformation, and either
directly or indirectly, the ligand binding properties of the
heterodimeric complex. This is in accord with studies from other
integrins that have implicated a -turn in a homologous region as
important in ligand binding. Thus, the Leu214Pro mutation appears to
produce the Glanzmann thrombasthenia phenotype by both qualitative and quantitative abnormalities. In addition, the mutation appears to confer
susceptibility of the GPIIb subunit to proteolysis.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1562-1571
© 1998 by The American Society of Hematology.
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