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


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 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.

SUBMITTER: Sims MC 

PROVIDER: S-EPMC7582559 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Sims Matthew C MC   Mayer Louisa L   Collins Janine H JH   Bariana Tadbir K TK   Megy Karyn K   Lavenu-Bombled Cecile C   Seyres Denis D   Kollipara Laxmikanth L   Burden Frances S FS   Greene Daniel D   Lee Dave D   Rodriguez-Romera Antonio A   Alessi Marie-Christine MC   Astle William J WJ   Bahou Wadie F WF   Bury Loredana L   Chalmers Elizabeth E   Da Silva Rachael R   De Candia Erica E   Deevi Sri V V SVV   Farrow Samantha S   Gomez Keith K   Grassi Luigi L   Greinacher Andreas A   Gresele Paolo P   Hart Dan D   Hurtaud Marie-Françoise MF   Kelly Anne M AM   Kerr Ron R   Le Quellec Sandra S   Leblanc Thierry T   Leinøe Eva B EB   Mapeta Rutendo R   McKinney Harriet H   Michelson Alan D AD   Morais Sara S   Nugent Diane D   Papadia Sofia S   Park Soo J SJ   Pasi John J   Podda Gian Marco GM   Poon Man-Chiu MC   Reed Rachel R   Sekhar Mallika M   Shalev Hanna H   Sivapalaratnam Suthesh S   Steinberg-Shemer Orna O   Stephens Jonathan C JC   Tait Robert C RC   Turro Ernest E   Wu John K M JKM   Zieger Barbara B   Kuijpers Taco W TW   Whetton Anthony D AD   Sickmann Albert A   Freson Kathleen K   Downes Kate K   Erber Wendy N WN   Frontini Mattia M   Nurden Paquita P   Ouwehand Willem H WH   Favier Remi R   Guerrero Jose A JA  

Blood 20201001 17


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  ...[more]

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