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 d isorder, caused by a quantitative or qualitative defect of the GPIIb-I IIa integrin (alpha(IIb)beta(3)), which functions as the platelet fibr inogen receptor. We report a case of type I GT due to a homozygous mut ation 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 transmembra ne and intracytoplasmic domains, Cotransfection of an expression vecto r containing the mutant GPIIb and wild-type GPIIIa showed that the mut ant Ser 870 --> stop GPIIb was able to associate to GPIIIa. However, t his heterodimer failed to mature as shown by endoglycosidase-H digesti on and was therefore not expressed at the COS-7 cell surface. This rep ort is the first description of a homozygous nonsense mutation in the GPIIb gene and highlights the role of the GPIIb light chain.