title: Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations.
abstract: Type IIA von Willebrand disease (vWD) results from abnormalities in von Willebrand factor (vWF) characterized by absence of plasma high molecular weight (HMW) vWF multimers. In this report, 5 distinct point mutations were identified in 6 Type IIA vWD families. A total of 7 mutations, all clustered within a 124-amino acid segment of the vWF A2 domain, now account for 9 of a panel of 11 Type IIA families. In COS-7 cells, 3 single amino acid substitutions, Val844----Asp, Ser743----Leu, and Gly742----Arg, impaired the transport of vWF multimers between the endoplasmic reticulum and the Golgi complex, with more profound effects on the secretion of HMW multimers than lower molecular weight forms. In contrast, 2 substitutions, Arg834----Trp and Gly742----Glu, resulted in secretion of HMW multimers similar to wild-type vWF. The vWF structure observed within patient platelets correlated closely with the synthesis pattern seen for the corresponding mutants in COS-7 cells. These findings demonstrate that structural alterations within the A2 domain of vWF can produce the characteristic phenotype of Type IIA vWD via two distinct molecular mechanisms.
authors.affiliation: Howard Hughes Medical Institute, Department of Human Genetics, University of Michigan Medical School, Ann Arbor 48109-0650.
authors.forename: S E
authors.initials: SE
authors.lastname: Lyons
authors.forename: M E
authors.initials: ME
authors.lastname: Bruck
authors.forename: E J
authors.initials: EJ
authors.lastname: Bowie
authors.forename: D
authors.initials: D
authors.lastname: Ginsburg
mesh_terms: D000596:Amino Acids / Q000235:genetics; D001483:Base Sequence; D001692:Biological Transport / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism; D002460:Cell Line; D016521:Electrophoresis, Gel, Pulsed-Field; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006056:Golgi Apparatus / Q000378:metabolism; D006596:Hexosaminidases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D014162:Transfection; D014842:von Willebrand Diseases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000596:Amino Acids; D006596:Hexosaminidases