title: Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, 9500 Gilman Drive 0625, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Lesley G
authors.initials: LG
authors.lastname: Ellies
authors.forename: David
authors.initials: D
authors.lastname: Ditto
authors.forename: Gallia G
authors.initials: GG
authors.lastname: Levy
authors.forename: Mark
authors.initials: M
authors.lastname: Wahrenbrock
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Dzung T
authors.initials: DT
authors.lastname: Le
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Marth
mesh_terms: D000818:Animals; D037263:Asialoglycoprotein Receptor; D017931:DNA Primers; D005169:Factor VIII / Q000378:metabolism; D006207:Half-Life; D006487:Hemostasis / Q000502:physiology*; D037102:Lectins; D008024:Ligands; D008657:Metabolic Clearance Rate; D051379:Mice; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics / Q000502:physiology*; D013921:Thrombocytopenia / Q000235:genetics / Q000628:therapy; D014158:Transcription, Genetic; D014841:von Willebrand Factor / Q000378:metabolism*; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D037263:Asialoglycoprotein Receptor; D017931:DNA Primers; D037102:Lectins; D008024:Ligands; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D005169:Factor VIII; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase