TY - JOUR
T1 - Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome
AU - Richards, Anna
AU - Kathryn Liszewski, M.
AU - Kavanagh, David
AU - Fang, Celia J.
AU - Moulton, Elizabeth
AU - Fremeaux-Bacchi, Veronique
AU - Remuzzi, Giuseppe
AU - Noris, Marina
AU - Goodship, Timothy H.J.
AU - Atkinson, John P.
N1 - Funding Information:
We would like to thank Madonna Bogacki for assistance with manuscript preparation. A.R. is supported by the Fulbright US/UK exchange programme and the Peel Medical Research Trust. D.K. is supported by Kidney Research UK and the Peel Medical Research Trust. T.H.J.G. is supported by the Foundation for Children with atypical HUS and the Robin Davies Trust. M.K.L. and J.P.A. are supported by NIH RO1 AI37618. C.J.F. is supported by NIH T32 AR07279. E.M. is supported by NIH T32 HL07317.
PY - 2007/1
Y1 - 2007/1
N2 - The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D + HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.
AB - The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D + HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.
KW - Alternative pathway of complement (AP)
KW - Atypical hemolytic uremic syndrome (aHUS)
KW - CD46)
KW - Cofactor activity (CA)
KW - Complement factor H (CFH)
KW - Factor I (IF)
KW - Membrane cofactor protein (MCP
KW - Renal transplantation
UR - http://www.scopus.com/inward/record.url?scp=33751035523&partnerID=8YFLogxK
U2 - 10.1016/j.molimm.2006.07.004
DO - 10.1016/j.molimm.2006.07.004
M3 - Article
C2 - 16882452
AN - SCOPUS:33751035523
SN - 0161-5890
VL - 44
SP - 111
EP - 122
JO - Molecular Immunology
JF - Molecular Immunology
IS - 1-3
ER -