A nonsense mutation in the GPIIb heavy chain (Ser 870-->stop) impairs platelet GPIIb-IIIa expression.
Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder, caused by a quantitative or qualitative defect of the GPIIb-IIIa integrin (alpha IIb beta 3), which functions as the platelet fibrinogen receptor. We report a case of type I GT due to a homozygous mutation resulting in Ser 870 to stop codon substitution. This residue is located near the proteolytic cleavage site of proGPIIb. The mutation results in a GPIIb truncated of 138 amino acids, including transmembrane and intracytoplasmic domains. Cotransfection of an expression vector containing the mutant GPIIb and wild-type GPIIIa showed that the mutant Ser 870-->stop GPIIb was able to associate to GPIIIa. However, this heterodimer failed to mature as shown by endoglycosidase-H digestion and was therefore not expressed at the COS-7 cell surface. This report is the first description of a homozygous nonsense mutation in the GPIIb gene and highlights the role of the GPIIb light chain.
Vinciguerra
C
C
Laboratoire d'Hémobiologie, Institut Pasteur, INSERM U331, Lyon, France.
Khelif
A
A
Alemany
M
M
Morle
F
F
Grenier
C
C
Uzan
G
G
Gulino
D
D
Dechavanne
M
M
Negrier
C
C
D000293:Adolescent; D015153:Blotting, Western; D018388:Codon, Terminator; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013915:Thrombasthenia / Q000235:genetics*
D018388:Codon, Terminator; D019039:Platelet Glycoprotein GPIIb-IIIa Complex