ABSTRACT
Thrombocytopenia absent radii (TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism (SNP) either at the 5' untranslated region (5'UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5'UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5'UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome.
Subject(s)
Genetic Variation , Hematopoiesis/genetics , Thrombocytopenia/genetics , Upper Extremity Deformities, Congenital/genetics , 5' Untranslated Regions/genetics , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Cohort Studies , Congenital Bone Marrow Failure Syndromes , Female , Humans , Infant , Infant, Newborn , Introns/genetics , Male , Platelet Count , Polymorphism, Single Nucleotide/genetics , RNA-Binding Proteins/genetics , Radius/pathology , Thrombocytopenia/diagnosis , Thrombocytopenia/pathology , Upper Extremity Deformities, Congenital/diagnosis , Upper Extremity Deformities, Congenital/pathology , Young AdultABSTRACT
Collagen receptors GPVI (also known as GP6) and integrin α2ß1 are highly expressed on blood platelets and megakaryocytes, their immediate precursors. After vessel injury, subendothelial collagen becomes exposed and induces platelet activation to prevent blood loss. Collagen types I and IV are thought to have opposite effects on platelet biogenesis, directing proplatelet formation (PPF) towards the blood vessels to prevent premature release within the marrow cavity. We used megakaryocytes lacking collagen receptors or treated megakaryocytes with blocking antibodies, and could demonstrate that collagen-I-mediated inhibition of PPF is specifically controlled by GPVI. Other collagen types competed for binding and diminished the inhibitory signal, which was entirely dependent on receptor-proximal Src family kinases, whereas Syk and LAT were dispensable. Adhesion assays indicate that megakaryocyte binding to collagens is mediated by α2ß1, and that collagen IV at the vascular niche might displace collagen I from megakaryocytes and thus contribute to prevention of premature platelet release into the marrow cavity and thereby directionally promote PPF at the vasculature.
