Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001004216 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Gray platelet syndrome (GPS) is a rare inherited bleeding disorder characterized by absence of platelet ɑ-granules and pathogenic variants in NBEAL2. To discern the spectrum of pathological features, we obtained genotype and phenotype data from 47 GPS patients and performed RNA sequencing and protein mass spectrometry on blood cells and plasma in a subset of these patients. We identified 37 novel GPS-causing variants in NBEAL2. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4-lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Finally, we show that the plasma proteome of GPS patients has increased levels of proteins associated with inflammation and immune response, 27% of which are synthesized outside of the hematopoietic system, predominantly in the liver.
2020-07-28 | PXD017227 | Pride
Project description:Gray Platelet Syndrome (GPS) is a rare recessive bleeding disorder resulting from biallelic variants in NBEAL2. As part of a comprehensive evaluation of the phenotype and genotype in 47 patients with GPS, four different blood cell-types (platelets, neutrophils, monocytes, and CD4-lymphocytes) were evaluated using bulk RNA-seq in five patients and five controls. These data are deposited in this archive in FASTQ format.
| EGAD00001005950 | EGA
Project description: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 NBEAL2, a member of the family of BEACH genes, are causal of GPS. The gene is involved in fusion, fission and trafficking of vesicles and granules. Whether NBEAL2 controls the ontogeny of granules of myeloid cells remains disputed. We found that neutrophils obtained from the peripheral blood from GPS patients have a normal distribution of azurophilic granules, but show a deficiency of specific granules, as confirmed by immuno-electron microscopy and mass spectrometry proteomics analyses. In cultures from peripheral CD34+ hematopoietic stem cells (HSCs) into mature neutrophils, the time dynamics showed concordance of NBEAL2 and specific granule protein expression at transcriptional and protein level, which were discordant in neutrophils obtained GPS-HSCs. This is indicative of normal granulopoiesis in GPS and identifies NBEAL2 as an important regulator of granule release (similar to platelets) which is suggested to occur upon egress into the blood stream. Patient neutrophil functions, including production of reactive oxygen species, chemotaxis and killing of bacteria and fungi were intact. Since GPS patients do not excessively suffer from infections, the consequence of the reduced specific granule content and lack of NET formation for innate immunity remains to be explored.
2021-01-28 | PXD017784 | Pride
Project description:Comparitive proteomics analyses of different cell types of blood i.e. platelets, neutrophils, monocytes and CD4 derived from the Gray platelet syndrome patients and their respective controls using TMT10plex reagents.
2020-07-23 | PXD016366 | Pride
Project description:Variants in NBEAL2 are causal of Grey Platelet Syndrome (GPS), a rare bleeding disorder characterized by absence of alpha- and specific- granules in platelets and neutrophils, respectively. The role of the scaffolding multidomain NBEAL2 protein in cell biology and granule homeostasis is unknown. We have performed proteomics to identify NBEAL2’s binding partners followed by different layers of validation including biochemical, cellular and functional analysis in vitro and in vivo.
2018-02-14 | PXD006091 | Pride
Project description:Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 76 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking
2023-05-12 | PXD042180 | JPOST Repository
Project description:The Neurobeachin-like 2 (Nbeal2) protein is a BEACH (beige and chediak-higashi) family member. Loss of function mutations of the human NBEAL2 gene result in development of the gray platelet syndrome (GPS) a bleeding disorder characterized by macrothrombocytopenia, splenomegaly, and paucity of α-granules in megakaryocytes, platelets, mast cells (MCs), neutrophils and NK cells. We found that Nbeal2 deficiency in MCs leads to an enhanced resistance to growth factor deprivation, dysregulated distribution of c-Kit and of the multidrug resistant protein-1 (ABCB1), as well as to a pro-inflammatory MC-phenotype. These characteristics are caused by a defective protein degradation machinery resulting in accumulation of RSK and ribosomal proteins (RPS). These data demonstrate that Nbeal2 prevents oncogenic transformation by controlling protein homeostasis (proteostasis) in MCs.
2024-02-06 | GSE225692 | GEO
Project description:As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, Grey Platelet Syndrome (GPS) is a rare congenital bleeding disorder caused by a reduction or absence of alpha granules in platelets. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.
| EGAS00001000091 | EGA
Project description:Loss of NBEAL2 function leads to grey platelet syndrome (GPS), a bleeding disorder characterized by macro-thrombocytopenia and α-granule-deficient platelets. A proportion of patients with GPS develop autoimmunity through an unknown mechanism, which might be related to the proteins NBEAL2 interacts with, specifically in immune cells. Here we show a comprehensive interactome of NBEAL2 in primary T cells, based on mass spectrometry identification of altogether 74 protein association partners. These include LRBA, a member of the same BEACH domain family as NBEAL2, recessive mutations of which cause autoimmunity and lymphocytic infiltration through defective CTLA-4 trafficking. Investigating the potential association between NBEAL2 and CTLA-4 signalling that is suggested by the mass spectrometry results, we confirm by co-immunoprecipitation that CTLA-4 and NBEAL2 interact with each-other. Interestingly, NBEAL2 deficiency leads to low CTLA-4 expression in patient-derived effector T cells, while their regulatory T cells appear unaffected. Knocking- down NBEAL2 in healthy primary T cells recapitulates the low CTLA-4 expression observed in T cells of GPS patients. Our results thus show that NBEAL2 is involved in the regulation of CTLA-4 expression in conventional T cells and provide a rationale for considering CTLA-4- immunoglobulin therapy in patients with GPS and autoimmune disease.
2023-05-12 | GSE196606 | GEO
Project description:Thromboinflammatory complications are well described sequalae of Coronavirus Disease 2019 (COVID-19), and there is evidence of both hyperreactive platelet and inflammatory neutrophil biology that contributes to the thromoinflammatory milieu. It has been demonstrated in other thromboinflammatory diseases that the circulating environment may affect cellular behavior, but what role this environment exerts on platelets and neutrophils in COVID-19 remains unknown. We tested the hypotheses that 1) plasma from COVID-19 patients can induce a prothrombotic platelet functional phenotype, and 2) contents released from platelets (platelet releasate) from COVID-19 patients can induce a proinflammatory neutrophil phenotype. We treated platelets with COVID-19 patient and disease control plasma and found that COVID-19 patient plasma promoted auto-aggregation, thereby reducing response to further stimulation ex-vivo. Neither disease condition increased the number of platelets adhered to a collagen and thromboplastin coated parallel plate flow chamber, but both markedly reduced platelet size. We treated healthy neutrophils with COVID-19 patient and disease control platelet releasate and found that COVID-19 patient platelet releasate increased myeloperoxidase-deoxyribonucleic acid complexes and induced changes to neutrophil gene expression. Together these results suggest aspects of the soluble environment of COVID-19 stimulate circulating platelets, and that the contents released from those platelets can elicit inflammatory neutrophil behavior independent of direct cellular contact.
2023-03-08 | GSE225217 | GEO