Nonsense mutation in exon-19 of GPIIb associated with thrombasthenic phenotype. Failure of GPIIb(delta597-1008) to form stable complexes with GPIIIa

Thromb Haemost. 2002 Apr;87(4):684-91.

Abstract

We report the molecular genetic analysis of a patient with thrombasthenic phenotype. The lack of surface platelet GPIIb-IIIa complexes and the presence of GPIIIa suggested it was a case of type I Glanzmann's thrombasthenia due to a mutation in GPIIb. Single stranded conformational polymorphism analysis (SSCP) of exon-19 of GPIIb showed polymorphic DNA bands. The DNA sequence of exon-19 revealed the presence of a homozygous C1882T transition that changes residue R597 to STOP codon. Since no other mutations were found in either GPIIb or GPIIIa it is concluded that the C1882T substitution in GPIIb is responsible for the thrombasthenic phenotype of the patient. The lack of platelet GPIIb-mRNA in the proband indicates instability of the [C1882T]GPIIb-mRNA. Coexpression of normal GPIIIa and GPIIb(delta597-1008) in CHO cells failed to show surface expression of GPIIb(delta597-1008)-IIIa complexes. Immunoprecipitation analysis demonstrated that GPIIb(delta597-1008) may indeed complex GPIIIa; however, the association is either unstable or incapable of progressing along the secretory pathway.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Child
  • Codon, Nonsense*
  • Codon, Terminator / genetics
  • Cricetinae
  • Cricetulus
  • DNA Mutational Analysis
  • Exons / genetics
  • Hemorrhagic Disorders / genetics*
  • Humans
  • Integrin beta3 / metabolism*
  • Male
  • Pedigree
  • Phenotype
  • Platelet Membrane Glycoprotein IIb / chemistry
  • Platelet Membrane Glycoprotein IIb / genetics*
  • Platelet Membrane Glycoprotein IIb / metabolism
  • Polymorphism, Single-Stranded Conformational
  • Precipitin Tests
  • Protein Interaction Mapping
  • RNA, Messenger / genetics
  • Recombinant Fusion Proteins / genetics
  • Sequence Deletion*
  • Thrombasthenia / genetics*
  • Transfection

Substances

  • Codon, Nonsense
  • Codon, Terminator
  • Integrin beta3
  • Platelet Membrane Glycoprotein IIb
  • RNA, Messenger
  • Recombinant Fusion Proteins