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A Three Amino Acid Deletion in Glycoprotein IIIa Is Responsible for Type I Glanzmann's Thrombasthenia: Importance of Residues Ile325Pro326Gly327 for  3 Integrin Subunit Association
Marie-Christine Morel-Kopp,
Cécile Kaplan,
Valérie Proulle,
Vincent Jallu,
Chantal Melchior,
Olivier Peyruchaud,
Marie-Hélène Aurousseau, and
Nelly Kieffer
From the Service d'Immunologie Leucoplaquettaire, GIP-INTS, Paris, France; UMR 5533 CNRS, Hôpital Cardiologique, Pessac, France; the Laboratoire d'Hématologie, Hôpital Jean Verdier, Bondy, France; and the Laboratoire Franco-Luxembourgeois de Recherche Biomédicale, Centre Universitaire, Luxembourg.
Glanzmann's thrombasthenia (GT) is a recessive autosomal bleeding disorder characterized by abnormal platelet aggregation due to a qualitative or quantitative defect of the glycoprotein (GP) IIb-IIIa complex (integrin  IIb 3). We describe a new mutation in the GPIIIa gene responsible for type I GT in a consanguineous Algerian family. A discordance between phenotyping and genotyping of the GPIIIa-related HPA-1 platelet alloantigen system in three family members heterozygous for the disease suggested a genetic defect in the GPIIIa gene and a normal GPIIb gene. Sequence analysis of amplified genomic DNA fragments showed a 6-bp deletion in exon 7 of the GPIIIa gene resulting in the amino acid deletion/substitution (Ile325Pro326Gly327  Met) and creating a new BspHI restriction site. Expression of the mutated integrin 3 subunit cDNA in Chinese hamster ovary cells showed that the cDNA gene was transcribed into a full-length 3 protein with an apparent molecular weight identical to wild-type 3 and accumulated as a single-chain molecule in the cell cytoplasm. The absence of heterodimeric complex formation of the mutant 3 protein with endogeneous v was shown by immunoprecipitation experiments, intracellular immunofluorescent labeling, and a semiquantitative enzyme-linked immunosorbent assay using the v3 complex-specific monoclonal antibodies LM609 and 23C6. Substitution of the methionine residue by a proline, present at position 326 of wild-type 3, did not restore the ability of the recombinant mutant 3 protein to associate with v, suggesting that the Ile-Pro-Gly motif is located in a 3 domain important for integrin subunit interaction. The association of a BspHI restriction site with this newly identified mutation has allowed allele-specific restriction analysis of Algerian GT individuals and the identification of two new unrelated type I patients exhibiting the same mutation, suggesting that the described mutation might be significant in this population and that BspHI restriction analysis will provide a useful screening assay for antenatal diagnosis and genetic counselling.
Blood, Vol. 90 No. 2 (July 15), 1997:
pp. 669-677
© 1997 by The American Society of Hematology.
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