Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands

Proc Natl Acad Sci U S A. 2002 Jul 23;99(15):10042-7. doi: 10.1073/pnas.142005099. Epub 2002 Jul 3.

Abstract

A number of poorly characterized genetic modifiers contribute to the extensive variability of von Willebrand disease, the most prevalent bleeding disorder in humans. We find that a genetic lesion inactivating the murine ST3Gal-IV sialyltransferase causes a bleeding disorder associated with an autosomal dominant reduction in plasma von Willebrand factor (VWF) and an autosomal recessive thrombocytopenia. Although both ST3Gal-IV and ST6Gal-I sialyltransferases mask galactose linkages implicated as asialoglycoprotein receptor ligands, only ST3Gal-IV deficiency promotes asialoglycoprotein clearance mechanisms with a reduction in plasma levels of VWF and platelets. Exposed galactose on VWF was also found in a subpopulation of humans with abnormally low VWF levels. Oligosaccharide branch-specific sialylation by the ST3Gal-IV sialyltransferase is required to sustain the physiologic half-life of murine hemostatic components and may be an important modifier of plasma VWF level in humans.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Asialoglycoprotein Receptor
  • DNA Primers
  • Factor VIII / metabolism
  • Half-Life
  • Hemostasis / physiology*
  • Lectins
  • Ligands
  • Metabolic Clearance Rate
  • Mice
  • Mutagenesis, Site-Directed
  • Polymerase Chain Reaction
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / therapeutic use
  • Recombinant Proteins / metabolism
  • Sialyltransferases / genetics
  • Sialyltransferases / physiology*
  • Thrombocytopenia / genetics
  • Thrombocytopenia / therapy
  • Transcription, Genetic
  • von Willebrand Factor / metabolism*

Substances

  • Asialoglycoprotein Receptor
  • DNA Primers
  • Lectins
  • Ligands
  • Receptors, Cell Surface
  • Recombinant Proteins
  • von Willebrand Factor
  • Factor VIII
  • Sialyltransferases
  • beta-galactoside alpha-2,3-sialyltransferase