Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Novara, Italy.
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
Blood Adv. 2022 Aug 9;6(15):4471-4484. doi: 10.1182/bloodadvances.2021006378.
Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.
钙库操纵性钙内流是一种细胞机制，当细胞内钙通道开放导致细胞内钙库耗竭时，它可以调节钙库的再填充。钙库操纵性钙内流的 2 个关键蛋白 STIM1 和 ORAI1 的功能获得性突变与几种超罕见疾病相关，这些疾病聚集为管状聚集肌病。我们的研究小组之前已经证明，携带 STIM1 p.I115F 突变的小鼠模型重现了 STIM1 功能获得性障碍的主要特征：肌肉无力和血小板减少症。在其他携带 STIM1 不同突变的小鼠中也发现了类似的发现。目前，这些患者尚无有效的治疗方法。在本研究中，我们报告了 CIC-39Na（一种钙库操纵性钙内流抑制剂）可以恢复血小板数量并对抗这些小鼠特征性的异常出血。在 STIM1 p.I115F 小鼠中观察到了细微的血小板生成差异，但野生型和 STIM1 p.I115F 小鼠之间的主要区别在于血小板清除率和血小板胞质基础钙水平。在用 CIC-39Na 治疗动物后，这两个指标都得到了恢复。这一发现为管状聚集肌病患者的血小板减少症提供了一种药理学治疗策略。
