title: Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome.
abstract: Genetic studies have shown that mutations of complement inhibitors such as membrane cofactor protein, Factors H, I, or B and C3 predispose patients to atypical hemolytic uremic syndrome (aHUS). Factor I is a circulating serine protease that inhibits complement by degrading C3b and up to now only a few mutations in the CFI gene have been characterized. In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI. Their overall clinical outcome was unfavorable, as half died or developed end-stage renal disease after their first syndrome episode. Eight patients with CFI mutations carried at least one additional known genetic risk factor for aHUS, such as a mutation in MCP, CFH, C3 or CFB; a compound heterozygous second mutation in CFI; or mutations in both the MCP and CFH genes. Five patients exhibited homozygous deletion of the Factor H-related protein 1 (CFHR-1) gene. Ten patients with aHUS had one mutation in their CFI gene (Factor I-aHUS), resulting in a quantitative or functional Factor I deficiency. Patients with a complete deletion of the CFHR-1 gene had a significantly higher risk of a bad prognosis compared with those with one Factor I mutation as their unique vulnerability feature. Our results emphasize the necessity of genetic screening for all susceptibility factors in patients with aHUS.
authors.affiliation: Cordeliers Research Center, INSERM UMRS 872, Paris, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bienaime
authors.forename: Marie-Agnes
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Regnier
authors.forename: Sara C
authors.initials: SC
authors.lastname: Nilsson
authors.forename: Wing H
authors.initials: WH
authors.lastname: Kwan
authors.forename: Jacques
authors.initials: J
authors.lastname: Blouin
authors.forename: Mathieu
authors.initials: M
authors.lastname: Jablonski
authors.forename: Nicolas
authors.initials: N
authors.lastname: Renault
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Rameix-Welti
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautés-Fridman
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D055815:Young Adult
chemical_list: D005340:Fibrinogen