Abstract：
MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance. The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections. The syndrome, usually diagnosed in the neonatal period because of severe thrombocytopenia, is caused by mutations in the MECOM gene, encoding for the transcription factor EVI1. The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood. In a paediatric patient affected by severe thrombocytopenia, we identified a novel variant of the MECOM gene (p.P634L), whose effect was tested on pAP-1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor. Moreover, we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT.
摘要：
MECOM相关综合征（MECOM-AS）是一种罕见疾病，其特征是变核细胞性血小板减少症，进行性骨髓衰竭,高外显率的全血细胞减少症和尺桡骨滑膜。临床表型还可能包括手指畸形，心脏和肾脏改变，听力损失,B细胞缺乏和感染倾向。综合症,通常在新生儿期被诊断为严重的血小板减少症，是由MECOM基因突变引起的,编码转录因子EVI1。EVI1功能改变与血小板减少症的相关机制尚不清楚。在患有严重血小板减少症的儿科患者中，我们确定了MECOM基因的新变体（p。P634L),在pAP-1增强子元件和靶基因的启动子上测试了其作用，表明突变损害了转录因子的抑制活性。此外，我们证明了EVI1控制MPL的转录调控，一种基因，其突变负责先天性阿米迦勒血小板减少症（CAMT），可能解释了MECOM-AS和CAMT之间的部分重叠。
