The role of Nbeal2 in the homeostasis and retention of granules in haematopoietic cells
type: CreativeWork
description: Gray platelet syndrome (GPS) is a rare disorder primarily characterised by the absence of α-granules in platelets. Typical clinical features of GPS include macrothrombocytopenia, abnormal or excessive bleeding, splenomegaly, and bone marrow fibrosis. GPS is caused by biallelic mutations in the NBEAL2 gene, where the deficiency of platelet α-granules is attributed to a loss of function in the Nbeal2 protein. Thus, the study of Nbeal2 can provide insight into both the clinical manifestations of GPS and the essential processes that contribute to the homeostasis of platelet α-granules. To this end, this work investigates the function of Nbeal2 through the study of a large collection of GPS patients through the NIHR BioResource-Rare Diseases (NBR-RD) programme, the Nbeal2−/− mouse model, and gene-edited Nbeal2−/− cell lines to understand its role in essential granule-related processes in haematopoietic cells. Through the NBR-RD GPS study, detailed clinical phenotypes were compared and patient blood samples were examined by Sysmex, RNA-Seq, and mass spectrometry analysis. The study revealed novel clinical phenotypes, including an array of autoimmune diseases and a prevalence of autoantibodies, differences in the transcriptomes and proteomes of GPS platelets, neutrophils, monocytes, and CD4+ lymphocytes, compared to healthy blood donors, as well as a pro-inflammatory signature in GPS plasma that may be mediated by changes in the liver. Loss of Nbeal2 function in GPS patients also affected the granularity and presence of granule-related proteins in leukocytes, which provides evidence that Nbeal2’s function is not exclusive to the regulation of platelet α-granules. This work also aimed to evaluate the mechanism by which Nbeal2 controls granule- related processes in haematopoietic cells. Subcellular fractionation of human and murine platelets revealed that Dock7, a known Nbeal2 binding partner, is mislocalised and has reduced expression in the platelets of GPS patients and Nb…
abstract: Gray platelet syndrome (GPS) is a rare disorder primarily characterised by the absence of α-granules in platelets. Typical clinical features of GPS include macrothrombocytopenia, abnormal or excessive bleeding, splenomegaly, and bone marrow fibrosis. GPS is caused by biallelic mutations in the NBEAL2 gene, where the deficiency of platelet α-granules is attributed to a loss of function in the Nbeal2 protein. Thus, the study of Nbeal2 can provide insight into both the clinical manifestations of GPS and the essential processes that contribute to the homeostasis of platelet α-granules. To this end, this work investigates the function of Nbeal2 through the study of a large collection of GPS patients through the NIHR BioResource-Rare Diseases (NBR-RD) programme, the Nbeal2−/− mouse model, and gene-edited Nbeal2−/− cell lines to understand its role in essential granule-related processes in haematopoietic cells. Through the NBR-RD GPS study, detailed clinical phenotypes were compared and patient blood samples were examined by Sysmex, RNA-Seq, and mass spectrometry analysis. The study revealed novel clinical phenotypes, including an array of autoimmune diseases and a prevalence of autoantibodies, differences in the transcriptomes and proteomes of GPS platelets, neutrophils, monocytes, and CD4+ lymphocytes, compared to healthy blood donors, as well as a pro-inflammatory signature in GPS plasma that may be mediated by changes in the liver. Loss of Nbeal2 function in GPS patients also affected the granularity and presence of granule-related proteins in leukocytes, which provides evidence that Nbeal2’s function is not exclusive to the regulation of platelet α-granules. This work also aimed to evaluate the mechanism by which Nbeal2 controls granule- related processes in haematopoietic cells. Subcellular fractionation of human and murine platelets revealed that Dock7, a known Nbeal2 binding partner, is mislocalised and has reduced expression in the platelets of GPS patients and Nb…
author: Mayer, Louisa
language: eng
keywords: Nbeal2, gray platelet syndrome, platelet granules
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2021-08-20
date modified: 2026-07-22T22:24:06Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.79579