Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.
Clin Genet. 2024 Sep;106(3):315-320. doi: 10.1111/cge.14547. Epub 2024 May 17.
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.
ANKRD26 5'UTR 中的变异是遗传性血小板减少症（ANKRD26-RT）的常见原因，与持续表达 ANKRD26 有关，该蛋白可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，所有报道的与 ANKRD26-RD 相关的变异都位于 RUNX1 结合位点和 22 个碱基对的侧翼区域内。在这里，我们报告了 ANKRD26 5'UTR 中的一个新变异，c.-107C>T。该变体位于 FLI1 结合位点，由于与 FLI1 失去氢键，预测会破坏 FLI1 结合。受影响的家族成员的分化 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，并且受影响的家族成员的血小板比对照血小板具有更高的 ANKRD26 表达。该变体增加了报告基因测定中 ANKRD26 启动子的活性。我们还提供了证据表明，先前报道的 c.-140C>G ANKRD26 5'UTR 变体是良性的，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 5'UTR 调节区的范围。
