Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands.
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.
Ellies
Lesley G
LG
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.
Ditto
David
D
Levy
Gallia G
GG
Wahrenbrock
Mark
M
Ginsburg
David
D
Varki
Ajit
A
Le
Dzung T
DT
Marth
Jamey D
JD
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
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