Inherited deficiencies of complement inhibitors
Complement has recently gained substantial worldwide attention, as it was discovered that several common diseases such as age-related macular degeneration (blindness in elderly) are related to deregulation of the balance between complement activation and inhibition. Full complement deficiencies lead to severe infectious and autoimmune diseases but are uncommon while it appears that we are just beginning to discover the associations between mutations and polymorphisms in complement proteins and several common diseases. This, in turn, enables us to consider complement as a pivotal target for novel therapies.
We are studying molecular basis of deficiencies and polymorphisms in complement inhibitors factor I, factor H, C4b-binding protein, membrane cofactor protein (CD46). These are found in hemolytic uremic syndrome, age-related macula degeneration, nephritis in systemic lupus erythematosus and recurrent pregnancy loss. Our goal is to relate these defects to clinical presentation to better understand normal human physiology as well as pathology of these diseases.
Finding of non-synonymous mutation in a protein does not necessarily mean that the mutation affects protein structure, secretion or function. This can be sometimes predicted but in most cases it must be evaluated by expressing a recombinant protein carrying the mutation and comparing its properties to the wild type. Therefore we have established expression systems for these proteins as well as panel of functional assays.