Inherited dysregulation of the complement system

In recent years there has been a substantial increase in the understanding of the genetics and pathogenesis of HUS. Mutations in factor H, a fluid-phase regulator of the alternative complement pathway, have been identified in 15-30% of patients with both familial and sporadic (D-) HUS. The mutations mainly cluster in the C terminal part of factor H, a region that is important for both binding to c3b and also polyanionic structures on cell surfaces. This leads to loss of protection against complement mediated endothelial injury. Mutations in the membrane bound complement regulator, membrane cofactor protein (MCP; CD46) have also been described in three families. These result in an impairment of inactivation of surface bound c3b. Finally mutations in the serine protease, factor I that lead to deficiency of the protein have been reported in two HUS patients. There is therefore now overwhelming evidence that dysregulation of the alternative complement pathway predisposes to the development of a thrombotic microangiopathy.