Discovering Novel Genetic Causes and Molecular Mechanisms of Atypical Hemolytic Uremic Syndrome

项目摘要 非典型溶血性尿毒综合征（阿胡斯，溶血性贫血，血小板减少症和急性肾功能衰竭， 不存在产志贺毒素E.大肠杆菌感染）是一种非常严重的疾病，通常是遗传性的。 许多导致这种疾病的基因突变已被发现在基因编码的组成部分， 补体级联，但最近我们发现了二酰甘油激酶ε基因的突变 （DGKE），表明补体外的因素，可能影响内皮细胞，涉及 阿胡斯并可能代表未来的治疗靶点。致病性遗传变异已被确定在约 其中50%的病例，另一半的病因尚未发现。在这个项目中，我们建议确定 使用下一代测序技术在大量患者中发现导致阿胡斯的新基因突变 并研究DGKE功能丧失如何影响内皮细胞的生物学， 转基因小鼠模型。

Project Summary Atypical hemolytic uremic syndrome (aHUS, hemolytic anemia, thrombocytopenia and acute renal failure in the absence of Shiga-toxin producing E. coli infection) is an extremely severe disease, frequently of genetic origin. Many genetic mutations causing this disease have been found in genes encoding components of the complement cascade, but more recently we have identified mutations in the gene diacylglycerol kinase epsilon (DGKE), indicating that factors outside of the complement, possibly affecting the endothelium, are implicated in aHUS and may represent future therapeutic targets. Pathogenic genetic variants have been identified in about 50% of these cases, leaving the etiology of the other half undiscovered. In this project we propose to identify mutations in novel genes that cause aHUS in an extensive cohort of patients using next generation sequencing and to study how DGKE loss of-function affects the biology of the endothelium causing aHUS by using transgenic mouse models.