Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome

Rensing‐Ehl, Anne; Pannicke, Ulrich; Zimmermann, Stefanie‐Yvonne; Lorenz, Myriam Ricarda; Neven, Bénédicte; Fuchs, Ilka; Salzer, Ulrich; Speckmann, Carsten; Strauss, Anne; Maaβ, Eberhard; Collet, B; Enders, Anselm; Favier, Rémi; Alessi, Marie‐Christine; Rieux-Laucat, Frédéric; Zieger, Barbara; Schwarz, Klaus; Ehl, Stephan

doi:10.1182/blood-2015-06-654145

Cited by 21 publications

(10 citation statements)

References 9 publications

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“…In summary, we show that Nbeal2 is a multifunctional protein regulating mitogenic signaling, cellcycle arrest, and mast cell effector functions. Together with a recent report that shows that a homozygous nonsense NBEAL2 mutation can mimic the clinical symptoms of the autoimmune lymphoproliferative syndrome (41), our data support the relevance of Nbeal2 in immunity above and beyond granule biosynthesis. Stimulation with SCF (S) leads to activation of STATs, which is regulated by Shp1.…”

Section: Discussionsupporting

confidence: 87%

The Neurobeachin-like 2 Protein Regulates Mast Cell Homeostasis

Drube

Grimlowski

Deppermann

et al. 2017

The Journal of Immunology

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The neurobeachin-like 2 protein (Nbeal2) belongs to the family of beige and Chediak-Higashi (BEACH) domain proteins. Loss-of-function mutations in the human gene or Nbeal2 deficiency in mice cause gray platelet syndrome, a bleeding disorder characterized by macrothrombocytopenia, splenomegaly, and paucity of α-granules in megakaryocytes and platelets. We found that in mast cells, Nbeal2 regulates the activation of the Shp1-STAT5 signaling axis and the composition of the c-Kit/STAT signalosome. Furthermore, Nbeal2 mediates granule formation and restricts the expression of the transcription factors, IRF8, GATA2, and MITF as well as of the cell-cycle inhibitor p27, which are essential for mast cell differentiation, proliferation, and cytokine production. These data demonstrate the relevance of Nbeal2 in mast cells above and beyond granule biosynthesis.

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Section: Discussionsupporting

confidence: 87%

The Neurobeachin-like 2 Protein Regulates Mast Cell Homeostasis

Drube

Grimlowski

Deppermann

et al. 2017

The Journal of Immunology

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“…Heparinized blood was obtained from patients with GPS and healthy adults after informed consent and according to the Declaration of Patients A to C, 2 from the same pedigree, have been previously described in Albers et al 1 Patients I to K, from the same pedigree, have been previously described in Rensing-Ehl et al 50 Patients A to G are also included in the study by Sims et al 26 Helsinki 2008 (Table 1). This study was approved by the Medical Ethical Committee of the Radboud University Medical Center (Nijmegen, The Netherlands).…”

Section: Patients With Gps Control Subjects and Cell Isolationmentioning

confidence: 99%

Neutrophil specific granule and NETosis defects in gray platelet syndrome

et al. 2021

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Gray platelet syndrome (GPS) is an autosomal recessive bleeding disorder characterized by a lack of α-granules in platelets and progressive myelofibrosis. Rare loss-of-function variants in neurobeachin-like 2 (NBEAL2), a member of the family of beige and Chédiak-Higashi (BEACH) genes, are causal of GPS. It is suggested that BEACH domain containing proteins are involved in fusion, fission, and trafficking of vesicles and granules. Studies in knockout mice suggest that NBEAL2 may control the formation and retention of granules in neutrophils. We found that neutrophils obtained from the peripheral blood from 13 patients with GPS have a normal distribution of azurophilic granules but show a deficiency of specific granules (SGs), as confirmed by immunoelectron microscopy and mass spectrometry proteomics analyses. CD34+ hematopoietic stem cells (HSCs) from patients with GPS differentiated into mature neutrophils also lacked NBEAL2 expression but showed similar SG protein expression as control cells. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as a potentially important regulator of granule release. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis, and killing of bacteria and fungi, were intact. NETosis was absent in circulating GPS neutrophils. Lack of NETosis is suggested to be independent of NBEAL2 expression but associated with SG defects instead, as indicated by comparison with HSC-derived neutrophils. Since patients with GPS do not excessively suffer from infections, the consequence of the reduced SG content and lack of NETosis for innate immunity remains to be explored.

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“…These mouse models of GPS highlight how platelet a-granule proteins intervene in tissue repair, cause an inflammatory state in the marrow and contribute to thromboinflammatory states in the circulation (e.g., cerebral ischemia) and facilitate cancer metastasis thereby further raising interest in the disease. 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.…”

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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Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome

Cited by 21 publications

References 9 publications

The Neurobeachin-like 2 Protein Regulates Mast Cell Homeostasis

The Neurobeachin-like 2 Protein Regulates Mast Cell Homeostasis

Neutrophil specific granule and NETosis defects in gray platelet syndrome

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

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