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

Matthew C Sims, Louisa Mayer, Janine H Collins, Tadbir K Bariana, Karyn Megy, Cecile Lavenu-Bombled, Denis Seyres, Laxmikanth Kollipara, Frances S Burden, Daniel Greene, Dave Lee, Antonio Rodriguez-Romera, Marie-Christine Alessi, William J Astle, Wadie F Bahou, Loredana Bury, Elizabeth Chalmers, Rachael Da Silva, Erica De Candia, Sri V V DeeviSamantha Farrow, Keith Gomez, Luigi Grassi, Andreas Greinacher, Paolo Gresele, Dan Hart, Marie-Françoise Hurtaud, Anne M Kelly, Ron Kerr, Sandra Le Quellec, Thierry Leblanc, Eva B Leinøe, Rutendo Mapeta, Harriet McKinney, Alan D Michelson, Sara Morais, Diane Nugent, Sofia Papadia, Soo J Park, John Pasi, Gian Marco Podda, Man-Chiu Poon, Rachel Reed, Mallika Sekhar, Hanna Shalev, Suthesh Sivapalaratnam, Orna Steinberg-Shemer, Jonathan C Stephens, Robert C Tait, Ernest Turro, NIHR BioResource


Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-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 B12 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.

Original languageEnglish
Issue number17
Pages (from-to)1956-1967
Number of pages12
Publication statusPublished - 22 Oct 2020


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