Complement susceptibility factors in atypical haemolytic uraemic syndrome, age related macular degeneration and ageing.

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Haemolytic uraemic syndrome (HUS) is usually a serious complication of infection with the bacteria E.Coli O157. This organism causes a severe gastrointestinal infection from which recovery is usual. However, 5-10% of patients develop kidney failure. This is secondary to a bacterial toxin which attaches itself to the lining of blood vessels in the kidney causing them to become blocked. Most patients recover but in a few the illness is severe enough to cause death. There is a rarer form of HUS , called atypical, which is not associated with E.Coli O157 infection. Atypical HUS (aHUS) has two variants, sporadic and familial. The sporadic form occurs often without any preceding illness but can be associated with use of certain drugs (most notably the oral contraceptive), pregnancy and HIV infection. Recovery of kidney function is less common and many patients require long term dialysis. In the familial form several members of a family will, over a period of time, be affected in a way similar to the sporadic form.We have found abnormalities in the genes for four proteins, called factor H, membrane cofactor protein, factor I and C3 in approximately 50% of aHUS. These all belong to a common group of proteins, named complement. They have an important role in allowing the body to differentiate between its own and foreign cells. If any of these genes is faulty then the body?s own cells can be damaged by mechanisms designed to destroy foreign cells.There is evidence that in a small number of patients with aHUS that there are faults in more than one of these genes. We have DNA samples from nearly 250 patients with aHUS and wish to screen all the known genes even in those patients in whom we have already found one fault.We have recently found that the structure of the chromosome on which these genes lies is in some individuals with aHUS rearranged to form new genes, the presence of which predispose to the disease. We have also found that such rearrangements can lead to loss of genes and that this can predispose to another more common disease called age related macular degeneration. This is the commonest form of blindness in the elderly and has been shown to be associated with the factor H gene. We now wish to determine what the biological effect of loss of these genes is and whether it is more common with increasing age.