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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 161-169
A Leu262Pro mutation in the integrin  3 subunit
results in an  IIb-3 complex that binds
fibrin but not fibrinogen
Christopher M. Ward,
Anita S. Kestin, and
Peter J. Newman
From the Blood Research Institute, The Blood Center of Southeastern
Wisconsin, Milwaukee, WI; the Department of Medicine, Brown University
School of Medicine, Providence, RI; and the Departments of Cellular
Biology and Pharmacology, Medical College of Wisconsin, Milwaukee, WI.
Platelet retraction of a fibrin clot is mediated by the platelet
fibrinogen receptor,  IIb 3. In certain
forms of the inherited platelet disorder, Glanzmann thrombasthenia
(GT), mutant IIb3 may interact normally
with fibrin yet fail to support fibrinogen-dependent aggregation. We
describe a patient (LD) with such a form of GT. Platelets from LD
supported normal clot retraction but failed to bind fibrinogen.
Platelet analysis using flow cytometry and immunoblotting showed
reduced but clearly detectable IIb3,
findings consistent with type II GT. Genotyping of LD revealed 2 novel 3 mutations: a deletion of nucleotides 867 to 868, resulting in a premature stop codon at amino acid residue 267, and a
T883C missense mutation, resulting in a leucine (Leu) 262-to-proline (Pro) substitution. Leu262 is highly conserved among integrin subunits and lies within an intrachain loop implicated in subunit association. Leu262Pro3 cotransfected with wild-type
IIb into COS-7 cells showed delayed intracellular
maturation and reduced surface expression of easily dissociable
complexes. In human embryonic kidney 293 cells,
Leu262Pro3 formed a complex with endogenous av and retracted fibrin clots similarly to wild-type
3. The same cells, however, were unable to bind
immobilized fibrinogen. The molecular requirements for
IIb3 to interact with fibrin compared with fibrinogen, therefore, appear to differ. The region surrounding 3 Leu262 may maintain 3 in a
fibrinogen-binding, competent form, but it appears not to be required
for receptor interactions with fibrin.
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