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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 180-188
A naturally occurring mutation near the amino terminus of  IIb
defines a new region involved in ligand binding to IIb 3
Ramesh B. Basani,
Deborah L. French,
Gaston Vilaire,
Deborah L. Brown,
Fangping Chen,
Barry S. Coller,
Jerry M. Derrick,
T. Kent Gartner,
Joel S. Bennett, and
Mortimer Poncz
From the Departments of Pediatrics and Medicine, University of
Pennsylvania School of Medicine, Philadelphia, PA; the Department of
Medicine, Mount Sinai School of Medicine, New York, NY; First
Affiliated Hospital, Hunan Medical University, Changsha, China; and
Microbiology and Molecular Cell Sciences, University of Memphis, TN.
Decreased expression of functional  IIb 3 complexes
on the platelet surface produces Glanzmann thrombasthenia. We have
identified mutations of IIbP145 in 3 ethnically distinct
families affected by Glanzmann thrombasthenia. Affected Mennonite and
Dutch patients were homozygous and doubly heterozygous, respectively,
for a P145A substitution, whereas a Chinese
patient was doubly heterozygous for a P145L substitution.
The mutations affect expression levels of surface IIb3 receptors
on their platelets, which was confirmed by co-transfection of
IIbP145A and 3 cDNA constructs in COS-1 cells.
Each mutation also impaired the ability of
IIb3 on affected platelets to interact with ligands. Moreover, when IIbP145A and 3 were stably coexpressed
in Chinese hamster ovary cells, IIb3 was readily detected on the
cell surface, but the cells were unable to adhere to immobilized
fibrinogen or to bind soluble fluorescein isothiocyanate-fibrinogen
after IIb3 activation by the activating monoclonal antibody
PT25-2. Nonetheless, incubating affected platelets with
the peptide LSARLAF, which binds to IIb, induced PF4 secretion,
indicating that the mutant IIb3 retained the ability to mediate
outside-in signaling. These studies indicate that mutations involving
IIbP145 impair surface expression of IIb3 and that
the IIbP145A mutation abrogates ligand binding to the
activated integrin. A comparative analysis of other IIb mutations
with a similar phenotype suggests that these mutations may cluster into
a single region on the surface of the IIb and may define a domain
influencing ligand binding. (Blood.
2000;95:180188)
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