GENETIC ABNORMALITIES OF COMPLEMENT REGULATORY MOLECULES IN HEMOLYTIC UREMIC SYNDROME

Hemolytic uremic syndrome (HUS) is the most frequent cause of acute renal failure of children. The disease may be caused by E. coli infections or may be of genetic origin (genetic HUS). In the latter, the clinical outcome is unfavorable with up to 50% of cases progressing to end-stage renal disease and 25% dying during the acute phase. Mutations in genes encoding factor H (CFH), membrane cofactor protein (MCP) and factor I (CFI) predispose to genetic HUS. These proteins are regulators of the activation of complement, a system involved in the immune defence against pathogens. The course and outcome of the disease are influenced by the gene involved. Of relevance CFH and CFI mutations are associated with a high incidence of disease recurrences on a transplanted kidney, whereas patients with MCP mutations have a favourable graft outcome. Recently mutations in C3 and complement factor B (CFB) have also been reported. The first objective of this study is to perform genetic screening in patients from the International Registry on HUS to provide genetic counselling which may help a better clinical management. Functional studies on the mutant proteins will be performed to investigate the role of the defects in the pathogenesis of HUS. Since the genetic defect underlying HUS is still unknown in about half of patients, we will search for other genes involved, by genetic and functional studies. CFH and MCP genes will also be studied in Stx-HUS patients as a genetic defect is these genes has been reported in two patients. A major issue of the research on genetic HUS is the availability of an experimental model, thus, a further aim of this proposal is to establish a mouse model of genetic HUS which will provide us with several novel insights into the functions of the CFH in protecting the kidney. It will hopefully allow achieving novel insights into the pathogenesis, diagnosis and therapies of HUS episodes and to investigate strategies to prevent recurrences on a kidney graft.