A novel 196 Leu to Pro substitution in the β3 subunit of the αIIbβ3 integrin in a patient with a variant form of Glanzmann thrombasthenia

Glanzmann thrombasthenia (GT) is an inherited disorder where an absence of platelet aggregation is associated with quantitative or qualitative abnormalities of the f IIb g 3 integrin. In rare patients, amino acid substitutions have provided information on the functional significance of specific domains within f IIb or g 3. We now report an elderly male GT patient (R.M.) from the south west of France whose platelets possess a small residual expression of f IIb g 3. Furthermore, the integrin failed to undergo the necessary conformational changes following platelet activation to permit the binding of fibrinogen or activation-dependent monoclonal antibodies despite the presence of an RGD-binding site. Screening of the f IIb and g 3 genes by PCR-SSCP revealed a heterozygous mutation at position 685 in exon 5 of the g 3 gene leading to a 196 Leu to Pro substitution. 196 Leu is a highly conserved amino acid of g 3. The other g 3 allele appeared to be silent. This mutation, inherited from his mother and present in other family members with intermediate levels of f IIb g 3, was close to the MIDAS-like domain of g 3, a fact that appears to explain its effect on f IIb g 3 activation and fibrinogen binding.