title: Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome.
abstract: Hemolytic-uremic syndrome (HUS) is a microvasculature disorder leading to microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Most cases of HUS are associated with epidemics of diarrhea caused by verocytotoxin-producing bacteria, but atypical cases of HUS not associated with diarrhea (aHUS) also occur. Early studies describing the association of aHUS with deficiencies of factor H suggested a role for this complement regulator in aHUS. Molecular evidence of factor H involvement in aHUS was first provided by Warwicker et al., who demonstrated that aHUS segregated with the chromosome 1q region containing the factor H gene (HF1) and who identified a mutation in HF1 in a case of familial aHUS with normal levels of factor H. We have performed the mutational screening of the HF1 gene in a novel series of 13 Spanish patients with aHUS who present normal complement profiles and whose plasma levels of factor H are, with one exception, within the normal range. These studies have resulted in the identification of five novel HF1 mutations in four of the patients. Allele HF1 Delta exon2, a genomic deletion of exon 2, produces a null HF1 allele and results in plasma levels of factor H that are 50% of normal. T956M, W1183L, L1189R, and V1197A are missense mutations that alter amino acid residues in the C-terminal portion of factor H, within a region--SCR16-SCR20--that is involved in the binding to solid-phase C3b and to negatively charged cellular structures. This remarkable clustering of mutations in HF1 suggests that a specific dysfunction in the protection of cellular surfaces by factor H is a major pathogenic condition underlying aHUS.
authors.affiliation: Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, 28006-Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Pérez-Caballero
authors.forename: C
authors.initials: C
authors.lastname: González-Rubio
authors.forename: M E
authors.initials: ME
authors.lastname: Gallardo
authors.forename: M
authors.initials: M
authors.lastname: Vera
authors.forename: M
authors.initials: M
authors.lastname: López-Trascasa
authors.forename: S
authors.initials: S
authors.lastname: Rodríguez de Córdoba
authors.forename: P
authors.initials: P
authors.lastname: Sánchez-Corral
mesh_terms: D001483:Base Sequence; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H; D004247:DNA