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Blood, 15 August 2001, Vol. 98, No. 4, pp. 1063-1069
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Identification of a region in glycoprotein IIIa involved in
subunit association with glycoprotein IIb: further lessons from
Iraqi-Jewish Glanzmann thrombasthenia
Rivka Yatuv,
Nurit Rosenberg,
Ariella Zivelin,
Hava Peretz,
Rima Dardik,
Luba Trakhtenbrot, and
Uri Seligsohn
From the Institute of Thrombosis and Hemostasis,
Department of Hematology, The Chaim Sheba Medical Center, Tel-Hashomer
and Sackler Faculty of Medicine, Tel-Aviv University, Israel.
The most frequent mutation causing Glanzmann thrombasthenia
in Iraqi-Jews (IJ-1) is an 11-bp deletion in exon 13 of the
glycoprotein (GP) IIIa gene. This deletion predicts a frameshift that
results in the elimination of the C406-C655 disulfide bond and a
premature termination codon shortly before the transmembrane domain. To determine the contribution of each of these alterations to the thrombasthenic phenotype, Chinese hamster ovary or baby hamster kidney
cells were cotransfected with normal GPIIb complementary DNA (cDNA) and
the following GPIIIa cDNAs: normal, cDNA bearing IJ-1 mutation,
2011T>A mutated cDNA predicting C655S (single-letter amino
acid codes) substitution, and 2019A>T mutated cDNA predicting Stop657.
Elimination of the C406-C655 disulfide bond by C655S substitution did
not affect GPIIb/IIIa surface expression or binding of the transfected
cells to immobilized fibrinogen, whereas elimination of the
transmembrane and cytoplasmic domains in IJ-1 and Stop657 mutants
prevented both surface expression and binding of the transfected cells
to immobilized fibrinogen. Immunohistochemical staining and
immunoprecipitation demonstrated that the elimination of amino acids
657-762 in IJ-1 and Stop657 prevented intracellular GPIIb/IIIa complex
formation, and differential immunofluorescence staining of GPIIIa and
cellular organelles suggested that the truncated uncomplexed GPIIIa
protein was retained in the endoplasmic reticulum. Because the use of
GPIIIa Stop693 and normal GPIIb cDNAs yielded GPIIb/IIIa complex
formation, though with lower efficiency, it is suggested that amino
acids 657-692 of GPIIIa are essential for the intracellular association
of GPIIb and GPIIIa.
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