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

溶血性尿毒综合征（HUS）通常是大肠杆菌O157感染的严重并发症。这种微生物引起严重的胃肠道感染，通常会恢复。然而，5-10%的患者会出现肾衰竭。这是继发于一种细菌毒素，它附着在肾脏血管内壁上，导致血管阻塞。大多数病人都能康复，但也有少数病人病情严重到足以导致死亡。有一种罕见的溶血性尿毒综合征，称为非典型溶血性尿毒综合征，它与大肠杆菌O157感染无关。非典型溶血性尿毒综合征（aHUS）有两种变体，散发性和家族性。散发形式通常在没有任何疾病的情况下发生，但可能与使用某些药物（最明显的是口服避孕药）、怀孕和艾滋病毒感染有关。肾功能恢复不太常见，许多患者需要长期透析。在家族性形式中，一个家庭的几个成员在一段时间内会以类似于散发性形式的方式受到影响。我们在大约50%的aHUS患者中发现了四种蛋白质的基因异常，分别是因子H、膜辅因子蛋白、因子I和C3。这些都属于一组共同的蛋白质，称为补体。它们在让身体区分自身细胞和外来细胞方面起着重要作用。如果这些基因中的任何一个有缺陷，那么身体呢？我们自己的细胞可以被设计用来破坏外来细胞的机制所破坏。有证据表明，在少数aHUS患者中，这些基因中有一个以上的缺陷。我们有来自近250名aHUS患者的DNA样本，并希望筛选所有已知的基因，即使在那些我们已经发现一个错误的患者中。我们最近发现，这些基因所在的染色体结构在一些患有aHUS的个体中被重排形成新的基因，这些基因的存在使这种疾病易感。我们还发现，这样的重排会导致基因丢失，这可能会导致另一种更常见的疾病，即年龄相关性黄斑变性。这是老年人最常见的失明形式，已被证明与因子H基因有关。我们现在希望确定这些基因丧失的生物学效应是什么，以及它是否随着年龄的增长而更常见。

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.