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)

1 CAM - University of Cambridge [UK]
2 CHU Trousseau [APHP]
3 Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V.
4 University of Manchester [Manchester]
5 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
6 SBU - Stony Brook University [SUNY]
7 UNIPG - Università degli Studi di Perugia = University of Perugia
8 Royal Hospital for Sick Children [Edinburgh]
9 Catholic University School of Medicine
10 Royal Free London NHS Foundation Trust
11 Universitätsmedizin Greifswald
12 QMUL - Queen Mary University of London
13 Hôpital Trousseau
14 Ninewells Hospital and Medical School [Dundee]
15 HCL - Hospices Civils de Lyon
16 Rigshospitalet [Copenhagen]
17 HMS - Harvard Medical School [Boston]
18 Centro Hospitalar Universitário do Porto
19 Children's Hospital of Orange County
20 UC - University of California
21 UNIMI - Università degli Studi di Milano = University of Milan
22 University of Calgary
23 MAHSC - Manchester Academic Health Science Centre
24 BGU - Ben-Gurion University of the Negev
25 TAU - Tel Aviv University
26 Glasgow Royal Infirmary
27 UBC - University of British Columbia
28 University of Freiburg [Freiburg]
29 VU University Medical Center [Amsterdam]
30 University of Aberdeen
31 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
32 UWA - The University of Western Australia
33 Hôpital Xavier Arnozan

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.

Keywords: BEACH-DOMAIN; NBEAL2; PATHOGENICITY; PROTEINS; PROTEOME; CLASSIFICATION; ABNORMALITIES; ASSOCIATION; GUIDELINES; NEUROBEACHIN-LIKE 2

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Human health and pathology

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⟩