title: BLOC-2 subunit HPS6 deficiency affects the tubulation and secretion of von Willebrand factor from mouse endothelial cells.
abstract: Hermansky-Pudlak syndrome (HPS) is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies (WPBs) are members of lysosome-related organelles (LROs) whose formation is regulated by HPS protein associated complexes such as BLOC (biogenesis of lysosome-related organelles complex) -1, -2, -3, AP-3 (adaptor protein complex-3) and HOPS (homotypic fusion and protein sorting complex). Von Willebrand factor (VWF) is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin (DDAVP) stimulation in HPS1 (BLOC-3 subunit), HPS6 (BLOC-2 subunit), and HPS9 (BLOC-1 subunit) deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.
authors.affiliation: Center for Medical Genetics, Beijing Children's Hospital, Capital Medical University, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Pediatric Disease Research, Beijing 100045, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College of London, London WC1E 6BT, UK.
authors.forename: Janos
authors.initials: J
authors.lastname: Kriston-Vizi
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College of London, London WC1E 6BT, UK. Electronic address: d.cutler@ucl.ac.uk.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Cutler
authors.affiliation: Center for Medical Genetics, Beijing Children's Hospital, Capital Medical University, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Pediatric Disease Research, Beijing 100045, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China. Electronic address: liwei@bch.com.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005838:Genotype; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D011487:Protein Conformation; D033921:Vesicular Transport Proteins / Q000172:deficiency*; D014841:von Willebrand Factor / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C554282:Hps6 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D033921:Vesicular Transport Proteins; D014841:von Willebrand Factor; D003894:Deamino Arginine Vasopressin
keywords: Biogenesis of lysosome-related organells complex; Hemostasis; Hermansky-Pudlak syndrome; Weibel-Palade bodies; von Willebrand factor