Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations
| Autor: | S E, Lyons, M E, Bruck, E J, Bowie, D, Ginsburg |
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| Rok vydání: | 1992 |
| Předmět: |
Blood Platelets
Base Sequence Molecular Sequence Data Golgi Apparatus Biological Transport Enzyme-Linked Immunosorbent Assay Endoplasmic Reticulum Transfection Polymerase Chain Reaction Precipitin Tests Cell Line Electrophoresis Gel Pulsed-Field von Willebrand Diseases Hexosaminidases Mutation Humans Amino Acids |
| Zdroj: | The Journal of biological chemistry. 267(7) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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