Identification of a homozygous single base pair deletion in the gene coding for the human platelet glycoprotein Ib alpha causing Bernard-Soulier syndrome

Thromb Haemost. 1994 Sep;72(3):444-9.

Abstract

Bernard-Soulier Syndrome (BSS) is a hereditary bleeding disorder which is caused by the absence or the dysfunction of the platelet glycoprotein Ib/IX/V (GP Ib/IX/V) complex, the major receptor for von Willebrand factor (vWf). BSS is characterized by the presence of giant platelets that show a reduced binding of vWf. Although BSS is a well-characterized disease, and many cases have been described in the literature, the molecular genetic basis of this disorder has been studied in only a few patients. We have studied the genetic basis of the defect in a BSS patient. Flow cytometric analysis of the platelet membrane glycoproteins revealed a significant decrease or absence of GP Ib alpha on the platelet surface, and low levels of GP V and GP IX. In subsequent immunoprecipitation experiments, we confirmed the presence of GP V (although in significantly decreased amounts) on the platelet surface. These results indicated a defect in the GP Ib alpha chain. Genomic DNA coding for GP Ib alpha was amplified, using the polymerase chain reaction (PCR). Subsequent direct sequence analysis demonstrated a homozygous deletion of T317 resulting in a frameshift deletion and predicting a substitution of Arg for Leu76. This deletion causes a shift in the reading frame, predicting a premature stop codon after 19 altered amino-acids, leading to a severily truncated molecule. The molecular genetic defect found in this patient differed from the mutations observed in three other BSS patients described in the literature. This points to a marked hetereogeneity of this disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Case Reports
  • Comparative Study

MeSH terms

  • Adult
  • Alleles
  • Amino Acid Sequence
  • Base Composition
  • Base Sequence
  • Bernard-Soulier Syndrome / genetics*
  • DNA Mutational Analysis
  • Female
  • Genes
  • Homozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Platelet Membrane Glycoproteins / deficiency
  • Platelet Membrane Glycoproteins / genetics*
  • Polymerase Chain Reaction
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics*
  • Sequence Alignment
  • Sequence Deletion*
  • von Willebrand Factor / metabolism

Substances

  • Platelet Membrane Glycoproteins
  • Receptors, Cell Surface
  • von Willebrand Factor
  • von Willebrand factor receptor