Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)

Abstract

Background. Atypical HUS (aHUS) is thought to be caused by predisposing mutations in genes encoding complement (regulating) proteins, such as Factor H (CFH), Factor I (IF), membrane co-factor protein (MCP) and Factor B (FB), or by auto-antibodies against CFH (αFH) in combination with a homozygous polymorphic deletion of the genes encoding Complement Factor H-related 1 and 3 (ΔCFHR1/3). The clinical impact of this knowledge is high, as it might be a prognostic factor for the outcome of renal transplantations and kidney donations.Methods. Mutational screening, by means of PCR and DNA sequencing, is performed in the above-mentioned genes in a group of 72 aHUS patients. Also, the presence of αFH and ΔCFHR1/3 was tested in patients and controls.Results. In 23 patients, a genetic aberration in at least one gene or the presence of αFH was found. A heterozygous mutation was observed in CFH in nine patients, in IF in seven patients and in MCP in three patients. No mutations were observed in FB. Seven patients presented αFH, of whom five also carried ΔCFHR1/3. Three patients carried a combined mutation (two patients: IF and MCP; one patient: IF, αFH and ΔCFHR1/3). A significant difference between patients and controls was detected for the presence of all three associated polymorphisms in CFH.Conclusions. Genetic abnormalities or the presence of αFH were detected in 31.9% of the aHUS patients. Furthermore, bigenic mutations were present, indicating that routine DNA mutation analysis of all complement factors associated with aHUS is important. © The Author 2010.