Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis.

Abstract:

:Bleeding problems are associated with defects in platelet alpha-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 adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules. Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of alpha-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 alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-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 alpha-granules but not for granule secretion.

journal_name

Blood

journal_title

Blood

authors

Lo B,Li L,Gissen P,Christensen H,McKiernan PJ,Ye C,Abdelhaleem M,Hayes JA,Williams MD,Chitayat D,Kahr WH

doi

10.1182/blood-2005-04-1356

subject

Has Abstract

pub_date

2005-12-15 00:00:00

pages

4159-66

issue

13

eissn

0006-4971

issn

1528-0020

pii

2005-04-1356

journal_volume

106

pub_type

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