Complement factor H and hemolytic uremic syndrome

Factor H is a 150 kDa single chain plasma glycoprotein that plays a pivotal role in the regulation of the alternative pathway of complement. Primary s equence analysis reveals a structural organization of this plasma protein, in 20 homologous units, called Short Consensus Repeats (SCRs). each about 6 0 amino acids long. Biochemical and genetic studies show an association bet ween factor H deficiency and human diseases, including Systemic Lupus Eryth ematosus. susceptibility to pyogenic infection and a form of menbranoprolif erative glomerulonephropathy. More recently, factor H deficiency has also b een associated with susceptibility to Hemolytic Uremic Syndrome (HUS), a di sease consisting of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure, caused by platelet thrombi which mainly, but not excl usively. form in the microcirculation of the kidney. In this review, we sum marize recent genetic and biochemical data, which indicate a critical role for factor H in the pathogenesis of HUS and suggest an important role of th e most C-terminal domain, i.e. SCR 20, in the disease. In addition, we disc uss the physiological consequences of these findings, as novel functional d ata show a particular essential role of SCR 20 of factor H as the central d iscriminatory and regulatory site of this multidomain, multifunctional plas ma protein. (C) 2001 Elsevier Science B.V. All rights reserved.