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

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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.