Double heterozygosity of the GPIIb gene in a Swiss patient with Glanzmann's thrombasthenia

• Published in: British journal of haematology 1998-09, Vol.102 (4), p.918-925
• Main Authors: Ruan, Jian, Peyruchaud, Olivier, Alberio, Lorenzo, Valles, GÉraldine, Clemetson, Kenneth, Bourre, FranÇois, Nurden, Alan T.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blotting, Western; Child, Preschool; double heterozygosity; Exons; Glanzmann's thrombasthenia; GPIIb gene; GPIIb–IIIa complexes; Hematologic and hematopoietic diseases; Hematology; Heterozygote; Humans; Male; Medical sciences; PCR‐SSCP; Pedigree; Platelet diseases and coagulopathies; Platelet Glycoprotein GPIIb-IIIa Complex - genetics; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Sequence Analysis, DNA; Thrombasthenia - genetics
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1998.00852.x

Glanzmann's thrombasthenia (GT) results from a qualitative or quantitative defect of GPIIb–IIIa complexes (integrin αIIbβ3), the fibrinogen receptor on platelets. This integrin plays a critical role in platelet aggregation. In this report we describe the molecular abnormalities of a patient with clinical and laboratory findings typical of type I Glanzmann's thrombasthenia. SDS‐PAGE with Western blotting revealed an absence of GPIIb but small amounts of normally migrating GPIIIa in his platelets. A non‐radioactive PCR‐SSCP procedure and direct sequence analysis of PCR‐amplified DNA fragments showed the patient to be a compound heterozygote for mutations in the GPIIb gene. A single point mutation (G to A) at nucleotide 1064 of the cDNA derived from the mother's allele led to a Glu324 to Lys amino acid substitution in GPIIb. It was responsible for a MscI restriction site in exon 12 of the GPIIb gene. This amino acid substitution changes the electric charge between the second and third Ca++‐binding domains of GPIIb. The second mutation was inherited from his father and is in exon 18 of the GPIIb gene. It was a T → C base transition at position 1787 of GPIIb cDNA and results in a Ile565 to Thr substitution. The two GPIIb mutations identified in this study will provide new information on GPIIb–IIIa structure and biosynthesis.