Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome

• Published in: Kidney international Vol. 77; no. 4; pp. 339 - 349
• Main Authors: Bienaime, Frank, Dragon-Durey, Marie-Agnes, Regnier, Catherine H., Nilsson, Sara C., Kwan, Wing H., Blouin, Jacques, Jablonski, Mathieu, Renault, Nicolas, Rameix-Welti, Marie-Anne, Loirat, Chantal, Sautés-Fridman, Catherine, Villoutreix, Bruno O., Blom, Anna M., Fremeaux-Bacchi, Veronique
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.02.2010; Nature Publishing Group; Elsevier Limited
• Subjects: Adolescent; alternative pathway; Biological and medical sciences; Child; Child, Preschool; Clinical Medicine; complement; complement Factor I; Female; Fibrinogen - genetics; Hematologic and hematopoietic diseases; hemolytic and; hemolytic and uremic syndrome; Hemolytic-Uremic Syndrome - genetics; Humans; Infant; Infant, Newborn; Klinisk medicin; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Mutation; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Platelet diseases and coagulopathies; Renal failure; thrombotic microangiopathy; uremic syndrome; Young Adult; complement Factor I; alternative pathway; hemolytic and uremic syndrome; thrombotic microangiopathy; complement; Nephrology; Prognosis; Cardiovascular disease; Hemopathy; Complement; Thrombohemolytic microangiopathy; Urology; Vascular disease; Hemolytic anemia; Genetics; Kidney disease; Thrombocytopenia; Urinary system disease; Serine endopeptidases; Hemolytic uremic syndrome; Enzyme; Acute; Complement Factor I; Peptidases; Platelet; alternative pathways; Renal failure; Risk factor; Hydrolases; Atypical; Mutation
• ISSN: 0085-2538; 1523-1755; 1523-1755
• DOI: 10.1038/ki.2009.472

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.