title: A novel 196Leu to Pro substitution in the beta3 subunit of the alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann thrombasthenia.
abstract: Glanzmann thrombasthenia (GT) is an inherited disorder where an absence of platelet aggregation is associated with quantitative or qualitative abnormalities of the alphaIIbbeta3 integrin. In rare patients, amino acid substitutions have provided information on the functional significance of specific domains within alphaIIb or beta3. We now report an elderly male GT patient (R.M.) from the south west of France whose platelets possess a small residual expression of alphaIIbbeta3. 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 alphaIIb and beta3 genes by PCR-SSCP revealed a heterozygous mutation at position 685 in exon 5 of the beta3 gene leading to a 196Leu to Pro substitution. 196Leu is a highly conserved amino acid of beta3. The other beta3 allele appeared to be silent. This mutation, inherited from his mother and present in other family members with intermediate levels of alphaIIbbeta3, was close to the MIDAS-like domain of beta3, a fact that appears to explain its effect on alphaIIbbeta3 activation and fibrinogen binding.
authors.affiliation: UMR 5533 CNRS, Hôpital Cardiologique, 33604 Pessac, France. Alan.Nurden@cnrshl.u-bordeaux2.fr
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.forename: Jian
authors.initials: J
authors.lastname: Ruan
authors.forename: Jean-Max
authors.initials: JM
authors.lastname: Pasquet
authors.forename: Bruno
authors.initials: B
authors.lastname: Gauthier
authors.forename: Robert
authors.initials: R
authors.lastname: Combrié
authors.forename: Thomas
authors.initials: T
authors.lastname: Kunicki
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005192:Family Health; D005340:Fibrinogen / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D007930:Leucine; D008297:Male; D015539:Platelet Activation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics* / Q000378:metabolism; D011392:Proline; D011485:Protein Binding / Q000235:genetics; D021122:Protein Subunits; D013915:Thrombasthenia / Q000097:blood / Q000235:genetics*
chemical_list: D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D021122:Protein Subunits; D005340:Fibrinogen; D011392:Proline; D007930:Leucine