title: Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree.
abstract: Mutations in the complement regulators factor H, membrane cofactor protein (MCP), and factor I are associated with atypical hemolytic uremic syndrome (aHUS, MIM 235400), suggesting that the disease develops as a consequence of the inefficient protection of the renal endothelium from damage by the complement system. Incomplete penetrance of the disease in individuals carrying these mutations is, however, relatively frequent. Here, we report the identification of a large, multiple affected aHUS pedigree in which there is independent segregation of three different aHUS risk factors: a MCP missense mutation (c.-598C>T; Pro165Ser) that decreases MCP expression on the cell surface, a dinucleotide insertion in the coding sequence of factor I (c.-1610insAT) that introduces a premature stop codon in the factor I protein, and the MCPggaac SNP haplotype block that was previously shown to decrease the transcription activity from the MCP promoter. Interestingly, individuals affected by aHUS in the pedigree are only those who have inherited the three aHUS risk factors. These data show an additive effect for mutations in MCP and factor I and provide definitive support to the conclusion that aHUS results from a defective protection of cellular surfaces from complement activation. Furthermore, they help to explain the incomplete penetrance of the disease, illustrating that concurrence of multiple hits in complement regulatory proteins may be necessary to significantly impair host tissue protection and to confer susceptibility to aHUS.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.forename: Elena Goicoechea de
authors.initials: EG
authors.lastname: Jorge
authors.forename: Cynthia Abarrategui
authors.initials: CA
authors.lastname: Garrido
authors.forename: Luis
authors.initials: L
authors.lastname: Carreras
authors.forename: Margarita
authors.initials: M
authors.lastname: López-Trascasa
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: Santiago Rodríguez
authors.initials: SR
authors.lastname: de Córdoba
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D020090:Chromosome Segregation / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics*; D017244:Complement Factor I / Q000737:chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree
chemical_list: D051916:Membrane Cofactor Protein; D017242:Complement Factor H; D017244:Complement Factor I