Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome.
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.
Bienaime
Frank
F
Cordeliers Research Center, INSERM UMRS 872, Paris, France.
Dragon-Durey
Marie-Agnes
MA
Regnier
Catherine H
CH
Nilsson
Sara C
SC
Kwan
Wing H
WH
Blouin
Jacques
J
Jablonski
Mathieu
M
Renault
Nicolas
N
Rameix-Welti
Marie-Anne
MA
Loirat
Chantal
C
Sautés-Fridman
Catherine
C
Villoutreix
Bruno O
BO
Blom
Anna M
AM
Fremeaux-Bacchi
Veronique
V
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
D005340:Fibrinogen