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

Matthew C Sims 1 Louisa Mayer 1 Janine H Collins 1 Tadbir K Bariana 1 Karyn Megy 1 Cecile Lavenu-Bombled 2 Denis Seyres 1 Laxmikanth Kollipara 3 Frances S Burden 1 Daniel Greene 1 Dave Lee 4 Antonio Rodriguez-Romera 1 Marie-Christine Alessi 5 William J Astle 1 Wadie F Bahou 6 Loredana Bury 7 Elizabeth Chalmers 8 Rachael da Silva 7 Erica de Candia 9 Sri V V Deevi 1 Samantha Farrow 1 Keith Gomez 10 Luigi Grassi 1 Andreas Greinacher 11 Paolo Gresele 7 Dan Hart 12 Marie-Françoise Hurtaud 13 Anne M Kelly 1 Ron Kerr 14 Sandra Le Quellec 15 Thierry Leblanc 13 Eva B Leinøe 16 Rutendo Mapeta 1 Harriet Mckinney 1 Alan D Michelson 17 Sara Morais 18 Diane Nugent 19 Sofia Papadia 1 Soo J Park 20 John Pasi 12 Gian Marco Podda 21 Man-Chiu Poon 22 Rachel Reed 23 Mallika Sekhar 1 Hanna Shalev 24 Suthesh Sivapalaratnam 1 Orna Steinberg-Shemer 25 Jonathan C Stephens 1 Robert C Tait 26 Ernest Turro 1 John K M Wu 27 Barbara Zieger 28 Taco W Kuijpers 29 Anthony D Whetton 4 Albert Sickmann 30 Kathleen Freson 31 Kate Downes 1 Wendy N Erber 32 Mattia Frontini 1 Paquita Nurden 33 Willem H Ouwehand 1 Remi Favier 13 Jose A Guerrero 1 
Abstract : Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet alpha-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B-12 levels. Novel clinical phenotypes were also observed, including 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 show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.
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Submitted on : Tuesday, March 9, 2021 - 2:35:56 PM
Last modification on : Tuesday, November 29, 2022 - 11:56:14 AM
Long-term archiving on: : Thursday, June 10, 2021 - 6:09:18 PM



Matthew C Sims, Louisa Mayer, Janine H Collins, Tadbir K Bariana, Karyn Megy, et al.. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood, 2020, 136 (17), pp.1956-1967. ⟨10.1182/blood.2019004776⟩. ⟨hal-03162108⟩



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