Abstract：
Variants in the 5\' UTR of ANKRD26 are a common cause of inherited thrombocytopenia (ANKRD26-RT), and are associated with sustained ANKRD26 expression, which inhibits megakaryocyte maturation and proplatelet formation. ANKRD26 expression is controlled by the binding of a RUNX1/FLI1 complex to the 5\' UTR. To date, all reported ANKRD26-RD associated variants have been within the RUNX1 binding site and a 22 base pair flanking region. Here, we report a novel variant in the 5\' UTR of ANKRD26, c.-107C>T. This variant is in the FLI1 binding site, and is predicted to disrupt FLI1 binding due to loss of a hydrogen bond with FLI1. Differentiated PBMCs from affected family members showed impaired megakaryocyte maturation and proplatelet formation and sustained expression of ANKRD26, and platelets from affected family members had higher ANKRD26 expression than control platelets. The variant increased activity of the ANKRD26 promotor in a reporter assay. We also provide evidence that the previously reported c.-140C>G ANKRD26 5\' UTR variant is benign and not associated with thrombocytopenia. Identification of the c.-107C>T variant extends the range of the regulatory region in the 5\' UTR of ANKRD26 that is associated with ANKRD26-RT.
摘要：
ANKRD26的5'UTR变异是遗传性血小板减少症（ANKRD26-RT）的常见原因，并与持续的ANKRD26表达有关，抑制巨核细胞成熟和前血小板形成。ANKRD26的表达受RUNX1/FLI1复合物与5'UTR结合的控制。迄今为止,所有报道的ANKRD26-RD相关变体均位于RUNX1结合位点和22个碱基对侧翼区内.这里,我们报告了ANKRD26的5'UTR中的一种新变体，c.-107C>T。该变体位于FLI1结合位点，并且预测由于与FLI1的氢键的丧失而破坏FLI1结合。来自受影响家庭成员的分化PBMC显示巨核细胞成熟和前血小板形成受损以及ANKRD26的持续表达，并且来自受影响家庭成员的血小板的ANKRD26表达高于对照血小板。变体在报告测定中增加了ANKRD26启动子的活性。我们还提供证据表明，先前报道的c.-140C>GANKRD265'UTR变异体是良性的，与血小板减少症无关。c.-107C>T变体的鉴定扩展了与ANKRD26-RT相关的ANKRD26的5'UTR中调控区的范围。
