A Ser162-->Leu mutation within glycoprotein (GP) IIIa (integrin beta3) results in an unstable alphaIIbbeta3 complex that retains partial function in a novel form of type II Glanzmann thrombasthenia.
Platelets from Glanzmann thrombasthenia patient BL express approximately 30% of the normal alphaIIbbeta3 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 beta3, resulting in a Ser162Leu amino acid substitution. This mutation appears to produce destabilizing effects on the alphaIIbbeta3 complex, as evidenced by the fact that (1) the BL alphaIIbbeta3 complex exhibited altered sedimentation velocity through sucrose gradients, (2) alphaIIb and beta3 was not recognized by complex-dependent monoclonal antibodies or co-precipitated by integrin subunit-specific antibodies, and (3) biosynthesis and trafficking of the alphaIIbbeta3Leu162 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 alphaIIbbeta3 complex.
Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee 53233-2194, USA.
D E
DE
Jackson
M M
MM
White
L K
LK
Jennings
P J
PJ
Newman
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000235:genetics*; D002648:Child; D006801:Humans; D039661:Integrin beta3; D016023:Integrins / Q000235:genetics*; D007930:Leucine; D008297:Male; D008969:Molecular Sequence Data; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D012694:Serine; D013915:Thrombasthenia / Q000235:genetics*
D015703:Antigens, CD; D039661:Integrin beta3; D016023:Integrins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D012694:Serine; D007930:Leucine