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Thromb Haemost 1998; 80(01): 42-48
DOI: 10.1055/s-0037-1615136
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A Ser162→ Leu Mutation within Glycoprotein (GP) IIIa (Integrin β3) Results in an Unstable αIIbβ3 Complex that Retains Partial Function in a Novel Form of Type II Glanzmann Thrombasthenia

Denise E. Jackson
1   Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI
,
Melanie M. White
2   Departments of Medicine and Biochemistry, The University of Tennessee Memphis, Memphis, TN
,
Lisa K. Jennings
2   Departments of Medicine and Biochemistry, The University of Tennessee Memphis, Memphis, TN
,
Peter J. Newman
1   Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee, WI
3   Departments of Cellular Biology and Pharmacology, Medical College of Wisconsin, Milwaukee, WI, USA
› Author AffiliationsThis work was presented in abstract form at the American Society of Hematology Meeting on December 9th, 1996 in Orlando, Florida. This investigation was supported by grants HL-44612 (PJN) and HL-53514 (LKJ) from the National Institutes of Health. Denise E. Jackson is a recipient of an American Heart Association (Wisconsin Affiliate) Postdoctoral Fellowship Award (96F-Post-34). Drs. Newman and Jennings held Established Investigator Awards from the American Heart Association during the course of this investigation.
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Publication History

Received 03 July 1997

Accepted after revision 28 March 1998

Publication Date:
08 December 2017 (online)

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Summary

Platelets from Glanzmann thrombasthenia patient BL express approximately 30% of the normal αIIbβ3 content and support fibrin-mediated clot retraction, but fail to bind fibrinogen or aggregate following cellular activation. BL platelets bind neither activation-dependent nor activation-independent ligands. DNA sequence analysis of BL platelet mRNA revealed a homozygous C583→T point mutation in a conserved region of β3, resulting in a Ser162Leu amino acid substitution. This mutation appears to produce destabilizing effects on the αIIbβ3 complex, as evidenced by the fact that (1) the BL αIIbβ3 complex exhibited altered sedimentation velocity through sucrose gradients, (2) αIIb and β3 was not recognized by complex-dependent monoclonal antibodies or co-precipitated by integrin subunit-specific antibodies, and (3) biosynthesis and trafficking of the αIIbβ3Leu162 complex was delayed relative to that of the wild-type control. Taken together, these data implicate the region encompassing Ser162 in the stabilization and ligand binding properties of the αIIbβ3 complex.

 

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