Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

Lee, Dong Heon; Yao, Chen; Bhan, Arunoday; Schlaeger, Thorsten M.; Keefe, Joshua; Rodriguez, Blanca; Hwang, Shih‐Jen; Chen, Ming-Huei; Levy, Daniel; Johnson, Andrew D.

doi:10.1101/854216

Cited by 2 publications

(2 citation statements)

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“…This suggests that the consequence of neutrophil emperipolesis by MKs is not only a BM phenomenon, but has ramifications for circulating platelets. Indeed, the transfer of membrane between MKs and neutrophils during emperipolesis has been recently reported 41 and a recent functional genomic study has suggested the association of Mpo, known to localize to neutrophil specific granules, with mean platelet volume highlighting the cross-talk between neutrophils and platelets 42 . Our proteomic dataset strongly supports the reduction of neutrophil specific granules in GPS, an observation that has previously been con-tested 12,13,18 , and shows for the first time that gelatinase granule constituents are also depleted from GPS neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Sims

Mayer

Collins

et al. 2020

Preprint

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Gray platelet syndrome (GPS) is a rare recessive disorder caused by variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet alpha-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. 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. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Sims

Mayer

Collins

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The transfer of membrane between MKs and neutrophils during emperipolesis has been reported, 55 and a recent functional genomic study reported an association of Mpo, known to localize to neutrophil-specific granules, with mean platelet volume highlighting the cross-talk between neutrophils and platelets. 56 Hence, the release of neutrophil granule proteins inside MKs during emperipolesis would provide a plausible explanation for the higher level of these proteins in GPS platelets.…”

Section: Discussionmentioning

confidence: 99%

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Sims

Mayer

Collins

et al. 2020

Blood

View full text Add to dashboard Cite

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet ɑ-granules, splenomegaly and bone marrow (BM) fibrosis. Due to its rarity, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathological features, we performed a detailed clinical genotypic and phenotypic study of 47 GPS patients. We identified 32 new etiological variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. We also observed novel clinical phenotypes; these include reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. 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. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data demonstrate that, in addition to the well-described platelet defects in GPS, there are also immune defects. The abnormal immune cells may be the drivers of systemic abnormalities, such as autoimmune disease.

show abstract

Integrative Genomic Analysis and Functional Studies Reveal GP5, GRN, MPO and MCAM as Causal Protein Biomarkers for Platelet Traits

Cited by 2 publications

References 58 publications

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome

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