TY - JOUR
T1 - The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation
AU - Kavanagh, D.
AU - Burgess, R.
AU - Spitzer, D.
AU - Richards, A.
AU - Diaz-Torres, M. L.
AU - Goodship, J. A.
AU - Hourcade, D. E.
AU - Atkinson, J. P.
AU - Goodship, T. H.J.
N1 - Funding Information:
This study was supported by grants from Kidney Research UK, the Northern Counties Kidney Research Fund, the Peel Medical Research Trust, the Robin Davies Trust and the Foundation for children with atypical HUS. DK is a Kidney Research UK training fellow. AR is a US/UK 2005/6 Fulbright Distinguished Scholar. JPA is supported by NIHRO1AI37618.
PY - 2007/5
Y1 - 2007/5
N2 - Hemolytic uremic syndrome is the clinical triad of thrombocytopenia, microangiopathic hemolytic anaemia and acute renal failure. Cases not associated with a preceding Shiga-like toxin producing Escherichia coli are described as atypical HUS (aHUS). Approximately 50% of patients with aHUS have mutations in one of three complement regulatory proteins, Factor H (CFH), membrane cofactor protein (MCP;CD46) or factor I (IF). A common feature of these three proteins is that they regulate complement by cofactor activity. Decay accelerating factor (DAF; CD55) regulates the complement system by disassociating the alternative and classical pathway convertases. Like CFH and MCP, the gene for DAF lies within the regulators of complement activation (RCA) gene cluster at 1q32. In 1998, we described linkage to this region in families with aHUS which led to the discovery of mutations in CFH and MCP. We therefore genotyped DAF in a panel of 46 aHUS patients including families with linkage to the RCA cluster. A mutation, I197V, was identified in one patient with familial HUS which was not found in 100 healthy controls. Molecular modelling of this mutation shows that the I197V mutation does not reside in an area which would be predicted to be important in decay accelerating activity. The expression of I197V on EBV-transformed B lymphocytes was equivalent to that of wild type controls. There was no significant decrease in decay acceleration activity of the recombinantly produced I197V mutant compared with wild type, as measured by a complement-mediated lytic assay. In conclusion, this study, identifies only one mutation in DAF in 46 patients with aHUS. This mutation, I197V, does not impair complement regulation and cannot be implicated in the pathogenesis of aHUS in this patient. This suggests that the complement regulatory abnormality in aHUS is principally one of deficient cofactor activity rather than of decay acceleration activity.
AB - Hemolytic uremic syndrome is the clinical triad of thrombocytopenia, microangiopathic hemolytic anaemia and acute renal failure. Cases not associated with a preceding Shiga-like toxin producing Escherichia coli are described as atypical HUS (aHUS). Approximately 50% of patients with aHUS have mutations in one of three complement regulatory proteins, Factor H (CFH), membrane cofactor protein (MCP;CD46) or factor I (IF). A common feature of these three proteins is that they regulate complement by cofactor activity. Decay accelerating factor (DAF; CD55) regulates the complement system by disassociating the alternative and classical pathway convertases. Like CFH and MCP, the gene for DAF lies within the regulators of complement activation (RCA) gene cluster at 1q32. In 1998, we described linkage to this region in families with aHUS which led to the discovery of mutations in CFH and MCP. We therefore genotyped DAF in a panel of 46 aHUS patients including families with linkage to the RCA cluster. A mutation, I197V, was identified in one patient with familial HUS which was not found in 100 healthy controls. Molecular modelling of this mutation shows that the I197V mutation does not reside in an area which would be predicted to be important in decay accelerating activity. The expression of I197V on EBV-transformed B lymphocytes was equivalent to that of wild type controls. There was no significant decrease in decay acceleration activity of the recombinantly produced I197V mutant compared with wild type, as measured by a complement-mediated lytic assay. In conclusion, this study, identifies only one mutation in DAF in 46 patients with aHUS. This mutation, I197V, does not impair complement regulation and cannot be implicated in the pathogenesis of aHUS in this patient. This suggests that the complement regulatory abnormality in aHUS is principally one of deficient cofactor activity rather than of decay acceleration activity.
KW - Complement
KW - Decay accelerating factor (DAF)
KW - Factor H (CFH)
KW - Factor I (CFI)
KW - Hemolytic uremic syndrome
KW - Membrane cofactor protein (MCP)
UR - http://www.scopus.com/inward/record.url?scp=34247243536&partnerID=8YFLogxK
U2 - 10.1016/j.molimm.2007.01.036
DO - 10.1016/j.molimm.2007.01.036
M3 - Article
C2 - 17368771
AN - SCOPUS:34247243536
SN - 0161-5890
VL - 44
SP - 3162
EP - 3167
JO - Molecular Immunology
JF - Molecular Immunology
IS - 12
ER -