遗传性血小板减少症（IT）是一类罕见单基因遗传病。因具有高度遗传异质性，其致病基因至今仍未完全阐明。课题组发现一个常染色体显性遗传IT家系，患者表现出巨核细胞成熟障碍。通过全外显子组测序技术及全基因组连锁分析发现一个新的IT基因TCEB3，并鉴定出一个新致病变异p.S732N，该变异可通过阻止巨核细胞多倍体形成而抑制其成熟，但具体机制有待阐明。分析显示该变异位于TCEB3转录延长功能结构域，该区域对Cyclin E转录水平具有正向调控作用，而Cyclin E是巨核细胞成熟关键调控因子。因此我们推测，p.S732N可能通过下调Cylin E转录水平，抑制巨核细胞成熟，从而导致血小板生成减少。本研究拟通过定点突变小鼠及体外诱导人/鼠源巨核细胞对TCEB3突变体的致病机制开展进一步研究，研究结果不仅有助于阐明这一新型IT发病机制，也可为揭示巨核细胞发育与血小板生成的关键调控机制提供新的方向。

Inherited thrombocytopenia (IT) is a kind of rare single-gene hereditary diseases. Since its highly genetic heterogeneity, the pathogenic genes are still not completely identified so far. We discovered an autosomal dominant IT parentage and the patients showed maturation disorder of megakaryocytes. By using exome sequencing and whole-genome genetic linkage analysis, we identified a new IT pathogenic gene TCEB3 and its pathogenic mutation p.S732N. The mutant can inhibit maturation of megakaryocyte through preventing the formation of polyploidy. However, the precise pathogenic mechanism remains to be elucidated. As the mutation was located in the elongation domain of TCEB3, which domain was critical for up-regulating the transcription of cyclin E, and cyclin E was indispensible for the maturation of megakaryocytes, we thus raised one hypothesis as follow. Through down-regulating the transcription of cyclin E, TCEB3-S732N impairs the maturation of megakaryocyte, and then causes reduced thrombopoiesis. We will investigate such a potential pathogenic mechanism of TCEB3-S732N in this novel IT by using point mutation mice and in vitro induced megakaryocytes from both human and mice. The results of the study will not only help to elucidate the pathogenesis of this new IT type, but can also provides a new direction for investigating the key regulations in the megakaryopoiesis and thrombopoiesis.