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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4159-4166.
Prepublished online as a Blood First Edition Paper on August 25, 2005; DOI 10.1182/blood-2005-04-1356.
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Submitted April 1, 2005
Accepted August 2, 2005
Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet  -granule biogenesis
Bryan Lo, Ling Li, Paul Gissen, Hilary Christensen, Patrick J McKiernan, Charles Ye, Mohamed Abdelhaleem, Jason A Hayes, Michael D Williams, David Chitayat, and Walter H Kahr*
Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
Section of Medical and Molecular Genetics, University of Birmingham, Birmingham Women's Hospital, Birmingham, United Kingdom; The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
The Liver Unit, Birmingham Children's Hospital, Birmingham, United Kingdom
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Department of Anesthesia, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
Department of Haematology, Birmingham Children's Hospital, Birmingham, United Kingdom
Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Department of Paediatrics, Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
* Corresponding author; email: walter.kahr{at}sickkids.ca.
Bleeding problems are associated with defects in platelet  -granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and ADP. Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of  -granules, and completely absent -granules. Soluble and membrane-bound -granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of -granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of -granules, moderately with late endosomes/lysosomes, minimally with -granules/lysosomes, and not with Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet -granules but not for granule secretion.
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