Functional Genomics for the Identification of Modulators of Platelet-Dependent Thrombus Formation

Abstract

Despite the absence of the genome in platelets, transcription profiling provides important insights into platelet function and can help clarify abnormalities in platelet disorders. The Bloodomics Consortium performed whole-genome expression analysis comparing in vitro–differentiated megakaryocytes (MKs) with in vitro–differentiated erythroblasts and different blood cell types. This allowed the identification of genes with upregulated expression in MKs compared with all other cell lineages, among the receptors BAMBI, LRRC32, ESAM, and DCBLD2. In a later correlative analysis of genome-wide platelet RNA expression with interindividual human platelet reactivity, LLRFIP and COMMD7 were additionally identified. A functional genomics approach using morpholino-based silencing in zebrafish identified various roles for all of these selected genes in thrombus formation. In this review, we summarize the role of the six identified genes in zebrafish and discuss how they correlate with subsequently performed mouse experiments.

Ultra-Rare Genetic Variation in Relapsing Polychondritis: A Whole-Exome Sequencing Study

“…but the sample size was too small to definitively conclude that these ultra-rare variants lead to a distinctive phenotype of RP. Animal and in-vitro studies have suggested that DCBLD2 is involved in cardiac function, vascular repair, and thrombosis (22)(23)(24)(25)(26). Recently, a child with a homozygous DCBLD2 stop-gained variant (W27*) was reported (27).…”

Ultra-rare genetic variation in relapsing polychondritis: a whole-exome sequencing study

“…Our study observed a numerically higher proportion of clinical features of MAGIC syndrome, including mucosal ulcerations and cardiovascular manifestations, in patients with DCBLD2 ultra-rare damaging QVs, but the sample size in this study was insufficient to definitively conclude whether these ultra-rare variants lead to a distinctive phenotype of RP. Animal and in vitro studies have suggested that DCBLD2 is involved in cardiac function, vascular repair and thrombosis 23–27. Recently, a child with a homozygous DCBLD2 stop-gained variant (W27*) was reported 28.…”

“…Animal and in vitro studies have suggested that DCBLD2 is involved in cardiac function, vascular repair and thrombosis. [23][24][25][26][27] Recently, a child with a homozygous DCBLD2 stop-gained variant (W27*) was reported. 28 This patient had severe restrictive cardiomyopathy, neurovascular malformation and skeletal abnormalities, and died at the age of 5.…”