Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase

We have identified altered lineage-specific expression of an N-acetylgalact osaminyltransferase gene, Galgt2, as the gain-of-function mechanism respons ible for the action of the Mvwf locus, a major modifier of plasma von Wille brand factor (VWF) level in RIIIS/J mice. A switch of Galgt2 gene expressio n from intestinal epithelial cell-specific to a pattern restricted to the v ascular endothelial cell bed leads to aberrant posttranslational modificati on and rapid clearance of WVF from plasma. Transgenic expression of Galgt2 directed to vascular endothelial cells reproduces the low VWF phenotype, co nfirming this switch in lineage-specific gene expression as the likely mole cular mechanism for Mvwf. These findings identify alterations in glycosyltr ansferase function as a potential general mechanism for the genetic modific ation of plasma protein levels.