TY - JOUR
T1 - Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome
AU - Bienaime, Frank
AU - Dragon-Durey, Marie-Agnes
AU - Regnier, Catherine H.
AU - Nilsson, Sara
AU - Kwan, Wing H.
AU - Blouin, Jacques
AU - Jablonski, Mathieu
AU - Renault, Nicolas
AU - Rameix-Welti, Marie-Anne
AU - Loirat, Chantal
AU - Sautes-Fridman, Catherine
AU - Villoutreix, Bruno O.
AU - Blom, Anna
AU - Fremeaux-Bacchi, Veronique
PY - 2010
Y1 - 2010
N2 - 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. Kidney International (2010) 77, 339-349; doi: 10.1038/ki.2009.472; published online 16 December 2009
AB - 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. Kidney International (2010) 77, 339-349; doi: 10.1038/ki.2009.472; published online 16 December 2009
KW - hemolytic and
KW - complement Factor I
KW - alternative pathway
KW - complement
KW - uremic syndrome
KW - thrombotic microangiopathy
U2 - 10.1038/ki.2009.472
DO - 10.1038/ki.2009.472
M3 - Article
C2 - 20016463
SN - 1523-1755
VL - 77
SP - 339
EP - 349
JO - Kidney International
JF - Kidney International
IS - 4
ER -