TY - JOUR
T1 - Genetics of HUS
T2 - The impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome
AU - Caprioli, Jessica
AU - Noris, Marina
AU - Brioschi, Simona
AU - Pianetti, Gaia
AU - Castelletti, Federica
AU - Bettinaglio, Paola
AU - Mele, Caterina
AU - Bresin, Elena
AU - Cassis, Linda
AU - Gamba, Sara
AU - Porrati, Francesca
AU - Bucchioni, Sara
AU - Monteferrante, Giuseppe
AU - Fang, Celia J.
AU - Liszewski, M. K.
AU - Kavanagh, David
AU - Atkinson, John P.
AU - Remuzzi, Giuseppe
PY - 2006/8/15
Y1 - 2006/8/15
N2 - Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non-Shiga toxin-associated HUS (non-Stx-HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx-HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.
AB - Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non-Shiga toxin-associated HUS (non-Stx-HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx-HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.
UR - http://www.scopus.com/inward/record.url?scp=33747159590&partnerID=8YFLogxK
U2 - 10.1182/blood-2005-10-007252
DO - 10.1182/blood-2005-10-007252
M3 - Article
C2 - 16621965
AN - SCOPUS:33747159590
VL - 108
SP - 1267
EP - 1279
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -