Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome
Abstract Gray platelet syndrome (GPS) is a rare recessive disorder caused by 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 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macro-thrombocytopenia, 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..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
bioRxiv.org - (2021) vom: 24. März Zur Gesamtaufnahme - year:2021 |
|---|
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| doi: |
10.1101/2020.03.23.20041467 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI017899052 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI017899052 | ||
| 003 | DE-627 | ||
| 005 | 20230429081903.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 200517s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2020.03.23.20041467 |2 doi | |
| 035 | |a (DE-627)XBI017899052 | ||
| 035 | |a (DE-599)biorXiv10.1101/2020.03.23.20041467 | ||
| 035 | |a (biorXiv)10.1101/2020.03.23.20041467 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | |a 570 |q DE-84 | |
| 100 | 1 | |a Sims, Matthew C |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Gray platelet syndrome (GPS) is a rare recessive disorder caused by 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 33 new causal variants in NBEAL2. Our GPS patient cohort exhibited known phenotypes, including macro-thrombocytopenia, 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. | ||
| 700 | 1 | |a Mayer, Louisa |e verfasserin |4 aut | |
| 700 | 1 | |a Collins, Janine H |e verfasserin |4 aut | |
| 700 | 1 | |a Bariana, Tadbir K |e verfasserin |4 aut | |
| 700 | 1 | |a Megy, Karyn |e verfasserin |4 aut | |
| 700 | 1 | |a Lavenu-Bombled, Cecile |e verfasserin |4 aut | |
| 700 | 1 | |a Seyres, Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Kollipara, Laxmikanth |e verfasserin |4 aut | |
| 700 | 1 | |a Burden, Frances S |e verfasserin |4 aut | |
| 700 | 1 | |a Greene, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Dave |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez-Romera, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Alessi, Marie-Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Astle, William J |e verfasserin |4 aut | |
| 700 | 1 | |a Bahou, Wadie F |e verfasserin |4 aut | |
| 700 | 1 | |a Bury, Loredana |e verfasserin |4 aut | |
| 700 | 1 | |a Chalmers, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Da Silva, Rachael |e verfasserin |4 aut | |
| 700 | 1 | |a De Candia, Erica |e verfasserin |4 aut | |
| 700 | 1 | |a Deevi, Sri V V |e verfasserin |4 aut | |
| 700 | 1 | |a Farrow, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Gomez, Keith |e verfasserin |4 aut | |
| 700 | 1 | |a Grassi, Luigi |e verfasserin |4 aut | |
| 700 | 1 | |a Greinacher, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Gresele, Paolo |e verfasserin |4 aut | |
| 700 | 1 | |a Hart, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Hurtaud, Marie-Françoise |e verfasserin |4 aut | |
| 700 | 1 | |a Kelly, Anne M |e verfasserin |4 aut | |
| 700 | 1 | |a Kerr, Ron |e verfasserin |4 aut | |
| 700 | 1 | |a Quellec, Sandra Le |e verfasserin |4 aut | |
| 700 | 1 | |a Leblanc, Thierry |e verfasserin |4 aut | |
| 700 | 1 | |a Leinøe, Eva B |e verfasserin |4 aut | |
| 700 | 1 | |a Mapeta, Rutendo |e verfasserin |4 aut | |
| 700 | 1 | |a McKin-ney, Harriet |e verfasserin |4 aut | |
| 700 | 1 | |a Michelson, Alan D |e verfasserin |4 aut | |
| 700 | 1 | |a Morais, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Nugent, Diane |e verfasserin |4 aut | |
| 700 | 1 | |a Papadia, Sofia |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Soo J |e verfasserin |4 aut | |
| 700 | 1 | |a Pasi, John |e verfasserin |4 aut | |
| 700 | 1 | |a Podda, Gian Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Poon, Man-Chiu |e verfasserin |4 aut | |
| 700 | 1 | |a Reed, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Sekhar, Mallika |e verfasserin |4 aut | |
| 700 | 1 | |a Shalev, Hanna |e verfasserin |4 aut | |
| 700 | 1 | |a Sivapalaratnam, Suthesh |e verfasserin |4 aut | |
| 700 | 1 | |a Steinberg-Shemer, Orna |e verfasserin |4 aut | |
| 700 | 1 | |a Stephens, Jonathan C |e verfasserin |4 aut | |
| 700 | 1 | |a Tait, Robert C |e verfasserin |4 aut | |
| 700 | 1 | |a Turro, Ernest |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, John K M |e verfasserin |4 aut | |
| 700 | 1 | |a Zieger, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Kuijpers, Taco W |e verfasserin |4 aut | |
| 700 | 1 | |a Whetton, Anthony D |e verfasserin |4 aut | |
| 700 | 1 | |a Sickmann, Albert |e verfasserin |4 aut | |
| 700 | 1 | |a Freson, Kathleen |e verfasserin |4 aut | |
| 700 | 1 | |a Downes, Kate |e verfasserin |4 aut | |
| 700 | 1 | |a Erber, Wendy N |e verfasserin |4 aut | |
| 700 | 1 | |a Frontini, Mattia |e verfasserin |4 aut | |
| 700 | 1 | |a Nurden, Paquita |e verfasserin |4 aut | |
| 700 | 1 | |a Ouwehand, Willem H |e verfasserin |4 aut | |
| 700 | 1 | |a Favier, Remi |e verfasserin |4 aut | |
| 700 | 1 | |a Guerrero, Jose A |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2021) vom: 24. März |
| 773 | 1 | 8 | |g year:2021 |g day:24 |g month:03 |
| 856 | 4 | 0 | |u https://doi.org/10.1182/blood.2019004776 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2020.03.23.20041467 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2021 |b 24 |c 03 | ||
| 953 | |2 045F |a 570 | ||