Gray platelet syndrome. Dissociation between abnormal sorting in megakaryocyte alpha-granules and normal sorting in Weibel-Palade bodies of endothelial cells.

Gébrane-Younès, Jeannine; Cramer, EM; Orcel, L; Caen, Jacques P.

doi:10.1172/jci116926

Cited by 37 publications

(21 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further exclude the possibility that NBEAL2 deficiency leads to defects in endothelial cells, we stained different tissues for VWF, an important Weibel-Palade body marker in endothelial cells of different origin. Endothelial cells in wild-type and knockout samples showed a punctate distribution of VWF (Supplemental Figure 3), further indicating a normal synthesis and storage in Nbeal2 -/-endothelial cells in line with previous results for patients with GPS (26).…”

Section: Figuresupporting

confidence: 90%

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

164

159

View full text Add to dashboard Cite

Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, α-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in α-granules are also thought to play a role in inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to gray platelet syndrome (GPS), a rare bleeding disorder characterized by macrothrombocytopenia, with platelets lacking α-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective α-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction following focal cerebral ischemia. In a model of excisional skin wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of α-granule secretion. This study demonstrates that platelet α-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.

show abstract

Section: Figuresupporting

confidence: 90%

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

164

159

View full text Add to dashboard Cite

show abstract

“…Abnormal VWF processing in megakaryocte ␣-granules but not in endothelial cells is also seen in the GPS. 54,55 The plasma-derived ␣-granule protein fibrinogen, which is normally acquired by megakaryocytes and platelets through ␣ IIb ␤ 3 -dependent endocytosis, [56][57][58] was also not detected in ARC platelets despite its normal presence in plasma. A deficiency of both megakaryocyte-synthesized (␤-TG, PF4, VWF, TSP-1) 37 and endocytosed (fibrinogen) soluble ␣-granule proteins further suggests that ARC megakaryocytes are unable to capture and package proteins into ␣-granule compartments, analogous to what is seen in the GPS.…”

Section: Discussionmentioning

confidence: 99%

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

2005

Blood

138

162

View full text Add to dashboard Cite

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 adenosine diphosphate (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 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 ␣-granules but not for granule secretion. IntroductionCongenital platelet disorders involving abnormalities in ␣ and/or dense (␦) granules are an important cause of inherited bleeding disorders. A number of genes have been linked to the ␦-granule defects associated with the Hermansky-Pudlak and ChediakHigashi syndromes, 1-6 and 16 genes have been identified in mice that regulate vesicle trafficking to platelet ␦-granules and melanosomes; some of these genes encode known vesicle trafficking proteins whereas others encode components of BLOC (biogenesis of lysosome-related organelles complexes) protein complexes. 3,7 Much less is known about the genes or proteins involved in ␣-granule defects, although some transcription factors and cellsurface glycoproteins have been implicated. For example, a family with X-linked macrothrombocytopenia and reduced ␣-granules was found to have an aspartate-to-glycine mutation in the transcription factor GATA1, 8 and hemizygous loss of the FLI1 transcription factor causes the Paris-Trousseau syndrome, characterized by abnormal megakaryocytes and giant ␣-granules. 9,10 In mice, loss of transcription factor NF-E2 expression produces abnormal megakaryocytes with absent ␣-granules, 11 and hematopoietic zinc finger (Hzf)-deficient mice have megakaryocytes and platelets with reduced ␣-granules and ␣-granule proteins. 12 Glycoprotein (GP) Ib␤-deficient mouse platelets contain abnormally large ␣-granules, 13 and giant ␣-granules have also been observed in platelets from a patient with Bernard-Soulier syndrome. 14 A deficiency of both platel...

show abstract

“…Indeed, the unimpaired formation of WPBs in CPE-deficient mice with defects in the biogenesis of ACTH-containing secretory granules (Methia et al, 1999) as well as in patients with gray platelet syndrome who possess abnormal platelet ␣-granvWF Pseudogranules in AtT-20 Cells ules, which normally contain vWF (Gebrane-Younes et al, 1993), suggests that formation of WPBs might be significantly different from that of other secretory granules.…”

Section: Acquisition Of Membrane Proteins By Vwf Pseudogranulesmentioning

confidence: 99%

Selective and Signal-dependent Recruitment of Membrane Proteins to Secretory Granules Formed by Heterologously Expressed von Willebrand Factor

Blagoveshchenskaya

Hannah

Allen

et al. 2002

MBoC

View full text Add to dashboard Cite

von Willebrand factor (vWF) is a large, multimeric protein secreted by endothelial cells and involved in hemostasis. When expressed in AtT-20 cells, vWF leads to the de novo formation of cigar-shaped organelles similar in appearance to the Weibel-Palade bodies of endothelial cells in which vWF is normally stored before regulated secretion. The membranes of this vWF-induced organelle, termed the pseudogranule, are uncharacterized. We have examined the ability of these pseudogranules, which we show are secretagogue responsive, to recruit membrane proteins. Coexpression experiments show that the Weibel-Palade body proteins P-selectin and CD63, as well as the secretory organelle membrane proteins vesicle-associated membrane protein-2 and synaptotagmin I are diverted away from the endogenous adrenocorticotropic hormone-containing secretory granules to the vWF-containing pseudogranules. However, transferrin receptor, lysosomal-associated membrane protein 1, and sialyl transferase are not recruited. The recruitment of P-selectin is dependent on a tyrosine-based motif within its cytoplasmic domain. Our data show that vWF pseudogranules specifically recruit a subset of membrane proteins, and that in a process explicitly driven by the pseudogranule content (i.e., vWF), the active recruitment of at least one component of the pseudogranule membrane (i.e., P-selectin) is dependent on residues of P-selectin that are cytosolic and therefore unable to directly interact with vWF.

show abstract

Gray platelet syndrome. Dissociation between abnormal sorting in megakaryocyte alpha-granules and normal sorting in Weibel-Palade bodies of endothelial cells.

Cited by 37 publications

References 33 publications

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice

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

Selective and Signal-dependent Recruitment of Membrane Proteins to Secretory Granules Formed by Heterologously Expressed von Willebrand Factor

Contact Info

Product

Resources

About