Cell Biology Program, Research Institute.
Division of Haematology/Oncology, The Hospital for Sick Children.
Curr Opin Hematol. 2019 Sep;26(5):313-319. doi: 10.1097/MOH.0000000000000525.
The increasing use of high throughput sequencing and genomic analysis has facilitated the discovery of new causes of inherited platelet disorders. Studies of these disorders and their respective mouse models have been central to understanding their biology, and also in revealing new aspects of platelet function and production. This review covers recent contributions to the identification of genes, proteins and variants associated with inherited platelet defects, and highlights how these studies have provided insights into platelet development and function.
Novel genes recently implicated in human platelet dysfunction include the galactose metabolism enzyme UDP-galactose-4-epimerase in macrothrombocytopenia, and erythropoietin-producing hepatoma-amplified sequence receptor transmembrane tyrosine kinase EPHB2 in a severe bleeding disorder with deficiencies in platelet agonist response and granule secretion. Recent studies of disease-associated variants established or clarified roles in platelet function and/or production for the membrane receptor G6b-B, the FYN-binding protein FYB1/ADAP, the RAS guanyl-releasing protein RASGRP2/CalDAG-GEFI and the receptor-like protein tyrosine phosphatase PTPRJ/CD148. Studies of genes associated with platelet disorders advanced understanding of the cellular roles of neurobeachin-like 2, as well as several genes influenced by the transcription regulator RUNT-related transcription factor 1 (RUNX1), including NOTCH4.
The molecular bases of many hereditary platelet disorders have been elucidated by the application of recent advances in cell imaging and manipulation, genomics and protein function analysis. These techniques have also aided the detection of new disorders, and enabled studies of disease-associated genes and variants to enhance understanding of platelet development and function.
高通量测序和基因组分析的广泛应用促进了遗传性血小板疾病新病因的发现。这些疾病及其各自的小鼠模型的研究对于理解其生物学特性至关重要，也揭示了血小板功能和生成的新方面。本综述涵盖了最近发现与遗传性血小板缺陷相关的基因、蛋白质和变异体的研究进展，并强调了这些研究如何深入了解血小板的发育和功能。
最近发现与人类血小板功能障碍相关的新基因包括巨血小板减少症中的半乳糖代谢酶 UDP-半乳糖-4-差向异构酶，以及血小板激动剂反应和颗粒分泌缺陷的严重出血性疾病中的促红细胞生成素产生肝细胞扩增序列受体跨膜酪氨酸激酶 EPHB2。最近对疾病相关变异体的研究确定或澄清了膜受体 G6b-B、FYN 结合蛋白 FYB1/ADAP、RAS 鸟苷释放蛋白 RASGRP2/CalDAG-GEFI 和受体样蛋白酪氨酸磷酸酶 PTPRJ/CD148 在血小板功能和/或生成中的作用。与血小板疾病相关的基因研究加深了对神经贝奇内尔样蛋白 2 以及受转录调节因子 runt 相关转录因子 1（RUNX1）影响的几个基因（包括 NOTCH4）的细胞作用的认识。
最近在细胞成像和操作、基因组学和蛋白质功能分析方面的进展阐明了许多遗传性血小板疾病的分子基础。这些技术还有助于发现新的疾病，并使疾病相关基因和变异体的研究能够提高对血小板发育和功能的理解。
