title: Structural and functional characterization of factor H mutations associated with atypical hemolytic uremic syndrome.
abstract: Genetic studies have demonstrated the involvement of the complement regulator factor H in nondiarrheal, nonverocytotoxin (i.e., atypical) cases of hemolytic uremic syndrome. Different factor H mutations have been identified in 10%-30% of patients with atypical hemolytic uremic syndrome (aHUS), and most of these mutations alter single amino acids in the C-terminal region of factor H. Although these mutations are considered to be responsible for the disease, the precise role that factor H plays in the pathogenesis of aHUS is unknown. We report here the structural and functional characterization of three different factor H proteins purified from the plasma of patients with aHUS who carry the factor H mutations W1183L, V1197A, or R1210C. Structural anomalies in factor H were found only in R1210C carriers; these individuals show, in their plasma, a characteristic high-molecular-weight factor H protein that results from the covalent interaction between factor H and human serum albumin. Most important, all three aHUS-associated factor H proteins have a normal cofactor activity in the proteolysis of fluid-phase C3b by factor I but show very low binding to surface-bound C3b. This functional impairment was also demonstrated in recombinant mutant factor H proteins expressed in COS7 cells. These data support the hypothesis that patients with aHUS carry a specific dysfunction in the protection of cellular surfaces from complement activation, offering new possibilities to improve diagnosis and develop appropriate therapies.
authors.affiliation: Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: David
authors.initials: D
authors.lastname: Pérez-Caballero
authors.forename: Olatz
authors.initials: O
authors.lastname: Huarte
authors.forename: Ari M
authors.initials: AM
authors.lastname: Simckes
authors.forename: Elena
authors.initials: E
authors.lastname: Goicoechea
authors.forename: Margarita
authors.initials: M
authors.lastname: López-Trascasa
authors.forename: Santiago Rodríguez
authors.initials: SR
authors.lastname: de Córdoba
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011485:Protein Binding
chemical_list: C493495:CFH protein, human; D003179:Complement C3b; D017242:Complement Factor H; D005340:Fibrinogen