VPS33B regulates protein sorting into and maturation of α-granule progenitor organelles in mouse megakaryocytes

Danai Bem, Holly Smith, Blerida Banushi, Jemima J Burden, Ian J White, Joanna Hanley, Nadia Jeremiah, Frédéric Rieux-Laucat, Ruth Bettels, Gema Ariceta, Andrew D Mumford, Steven G Thomas, Steve P Watson, Paul Gissen

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37 Citations (Scopus)


Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is caused by deficiencies in the trafficking proteins VPS33B or VIPAR, and is associated with a bleeding diathesis and a marked reduction in platelet α-granules. We generated a tamoxifen-inducible mouse model of VPS33B deficiency, Vps33b(fl/fl)-ER(T2), and studied the platelet phenotype and α-granule biogenesis. Ultrastructural analysis of Vps33b(fl/fl)-ER(T2) platelets identified a marked reduction in α-granule count and the presence of small granule-like structures in agreement with the platelet phenotype observed in ARC patients. A reduction of ∼65% to 75% was observed in the α-granule proteins von Willebrand factor and P-selectin. Although platelet aggregation responses were not affected, a defect in δ-granule secretion was observed. Under arteriolar shear conditions, Vps33b(fl/fl)-ER(T2) platelets were unable to form stable aggregates, and tail-bleeding measurement revealed a bleeding diathesis. Analysis of bone marrow-derived megakaryocytes (MKs) by conventional and immuno-electron microscopy from Vps33b(fl/fl)-ER(T2) mice revealed a reduction in mature type-II multivesicular bodies (MVB II) and an accumulation of large vacuoles. Proteins that are normally stored in α-granules were underrepresented in MVB II and proplatelet extensions. These results demonstrate that abnormal protein trafficking and impairment in MVB maturation in MKs underlie the α-granule deficiency in Vps33b(fl/fl)-ER(T2) mouse and ARC patients.

Original languageEnglish
Pages (from-to)133-143
Number of pages11
Issue number2
Early online date6 May 2015
Publication statusPublished - 9 Jul 2015

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© 2015 by The American Society of Hematology.


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