title: Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32.
abstract: The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.forename: Elena
authors.initials: E
authors.lastname: Goicoechea de Jorge
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Luis
authors.initials: L
authors.lastname: Carreras Berges
authors.forename: Margarita
authors.initials: M
authors.lastname: López-Trascasa
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D015703:Antigens, CD / Q000235:genetics; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D003167:Complement Activation / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins