Genetic screening in haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is a disease of diverse origin. The last year has witnessed the identification of a novel genetic marker of this disease, the description of the frequency of the factor H associated form of HUS in a registry of over 100 patients and a better understanding of the pathophysiology of the disease.

In patients with atypical HUS, heterozygous mutations in the gene coding for the soluble complement regulator factor H are reported and most of the mutations cluster in the C-terminal recognition domain of the protein. A novel genetic marker for HUS has also been identified. Mutations occurring in the gene of the von Willebrand factor cleaving protease, ADAMTS13, which were previously linked to thrombotic thrombocytopenic purpura have now been identified in HUS patients. The frequency of factor H-associated HUS was established as 14% in a registry of German speaking countries and also 16 novel disease associated mutations were reported. The pathophysiology of factor H-associated HUS was analysed. Three analysed mutant proteins show normal complement regulatory activities but display defective recognition functions: reduced binding to surface attached C3b, to heparin/polyanions and to endothelial cells.

The identification of effector molecules of the complement as well as the coagulation cascade as disease associated molecules indicate a regulatory protein network, which maintains integrity of endothelial cells during stress or infection. Defining the individual components and how their functional interaction causes microangiopathies will identify additional disease markers and will allow the design of proper diagnostic and therapeutic approaches.