Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome

The past decade has seen the identification of mutations in the genes for complement factor H ( CFH ) (1–6), membrane co-factor protein ( MCP ) (7–12), and factor I ( CFI ) (9,13–15) as predisposing factors for the development of atypical hemolytic uremic syndrome (aHUS). With this increased understanding of the genetic basis of aHUS and its implications for patient treatment, particularly transplantation, has come an increasing demand for genetic screening. A full analysis for mutations in all three of these complement proteins is expensive and time-consuming. A rational system is required to optimize the timely delivery of results and to reduce the cost of screening. We suggest some proposals that are based on our own experience with aHUS and our review of the relevant literature. The strategy that we propose (Figure 1) involves an initial screen that is based on protein levels (either serum levels or surface expression). This offers a rapid mechanism to identify the likely gene involved. In those in whom normal levels of complement regulators are found, we propose screening genes on the basis of their order of frequency of mutation detection ( CFH , approximately 30%; MCP , approximately 10%; CFI , 2 to 5%) (15). Furthermore, mutations cluster in certain exons of the genes that code for the protein (60% of CFH mutations cluster in complement control protein modules 19 and 20; 90% of MCP mutations in control protein modules 1 to 4; 60% of CFI mutations in the serine protease domain) (15). By screening these regions first, cost and detection time can be minimized. Figure 1. Flow diagram demonstrating screening strategy in atypical hemolytic uremic syndrome (aHUS). Our suggested screening strategy in aHUS involves a three-tier approach. Level 1 investigations provide a quantitative assessment of protein concentrations by radioimmunodiffusion assay (RIDA) or FACS. …