Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome

Kahr, Walter H.A.; Hinckley, Jesse D.; Li, Ling; Schwertz, Hansjörg; Christensen, Hilary; Rowley, Jesse W.; Pluthero, Fred G.; Urban, Denisa; Fabbro, Shay; Nixon, B. Tracy; Gadzinski, Rick; Storck, Mike; Wang, Kai; Ryu, Gi Yung; Jobe, Shawn M.; Schutte, Brian C.; Moseley, Jack; Loughran, Noeleen B.; Parkinson, John; Weyrich, Andrew S.; Paola, Jorge Di

doi:10.1038/ng.884

Cited by 239 publications

(186 citation statements)

References 14 publications

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“…Although the first description of a patient with GPS was reported in 1971 (32), it took until 2011 for NBEAL2 to be identified as the mutated gene causing the disease, a finding which thereby provided the molecular basis for detailed studies on the function and (patho-)physiological significance of α-granules, the most abundant organelles in platelets (19)(20)(21). Our study now provides compelling complementary evidence that NBEAL2 is essential for platelet α-granule biogenesis and establishes the Nbeal2 -/-mouse as a valuable animal model of GPS that recapitulates many of the symptoms found in patients with GPS.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

166

159

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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.

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Section: Discussionmentioning

confidence: 99%

“…Only recently, different mutations in the neurobeachin-like 2 (NBEAL2) gene have been identified in patients with GPS (19)(20)(21). NBEAL2 is a 302-kDa large member of the BEACH-WD40 domain protein family.…”

Section: Introductionmentioning

confidence: 99%

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

Deppermann¹,

Cherpokova²,

Nurden³

et al. 2013

J. Clin. Invest.

166

159

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show abstract

“…This was nicely illustrated in a recent study showing how GPS platelets are unable to deposit a-granule matrix proteins such as fibrinogen (Fg) and fibronectin or provide a a-granule-derived membrane pool for optimal platelet spreading and for consolidating platelet connections on microlesions of exposed subendothelium [9]. Notwithstanding the phenotypic variability, a large number of GPS families, all with autosomal recessive inheritance, genotyped with biallelic mutations in NBEAL2 [10][11][12][13]. Significantly, neurobeachin-like 2 (NBEAL2) is predicted to be scaffolding protein that intervenes in vesicle trafficking, it contains a Beige and ChediakHigashi (BEACH) domain also seen in lysosomal trafficking regulator (LYST) mutated in the Chediak-Higashi syndrome and associated with abnormal lysosomes and dense granules [14].…”

Section: Gray Platelet Syndrome and The Nbeal2 Genementioning

confidence: 98%

“…Quite recently, Rensing-Ehl et al [18] have reported that GPS can phenotypically mimic autoimmune lymphoproliferative syndrome (ALPS). Members of two families diagnosed with ALPS combined thrombocytopenia (or pancytopenia), enlarged "gray" platelets on blood smear, a much reduced platelet P-selectin expression after platelet activation with high plasma levels of vitamin B 12 and soluble Fas ligand (sFASL) often considered as a marker of inflammation and apoptosis. Yet, FAS mutations frequently seen in ALPS, were absent.…”

Section: Gray Platelet Syndrome and The Nbeal2 Genementioning

confidence: 99%

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

Nurden

2016

American J Hematol

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There is much current interest in the role of the platelet storage pool of α‐granule proteins both in hemostasis and non‐hemostatic events. As well as in the arrest of bleeding, the secreted proteins participate in wound healing, inflammation, and innate immunity while in pathology they may be actors in arterial thrombosis and atherosclerosis as well as cancer and metastasis. For a long time, gray platelet syndrome (GPS) has been regarded as the classic inherited platelet disorder caused by an absence of α‐granules and their contents. While NBEAL2 is the major source of mutations in GPS, other gene variants may give rise to significant α‐granule deficiencies in platelets. These include GATA1, VPS33B, or VIPAS39 in the arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome and now GFI1B. Nevertheless, many phenotypic differences are associated with mutations in these genes. This critical review was aimed to assess genotype/phenotype variability in disorders of platelet α‐granule biogenesis and to urge caution in grouping all genetic defects of α‐granules as GPS. Am. J. Hematol. 91:714–718, 2016. © 2016 Wiley Periodicals, Inc.

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“…Nonetheless, Kahr's group and others have recently demonstrated that mutations in NBEAL2, which encodes neurobeachin-like protein 2, cause GPS. [3][4][5] Even before this work, however, Kahr and colleagues had characterized another syndrome associated with ␣-granule deficiency termed arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. 6 ARC syndrome is a rare autosomal recessive condition characterized by death in the first year of life.…”

Section: ␣-Granules: a Story In The Making --------------------------mentioning

confidence: 99%

α-granules: a story in the making

Flaumenhaft¹

2012

Blood

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Mutations in NBEAL2, encoding a BEACH protein, cause gray platelet syndrome

Cited by 239 publications

References 14 publications

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

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

Should any genetic defect affecting α‐granules in platelets be classified as gray platelet syndrome?

α-granules: a story in the making

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