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Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome

Kavanagh, David; Richards, Anna; Noris, Marina; Hauhart, Richard; Liszewski, M Kathryn; Karpman, Diana LU ; Goodship, Judith A; Fremeaux-Bacchi, Veronique; Remuzzi, Giuseppe and Goodship, Timothy H J, et al. (2008) In Molecular Immunology 45(1). p.95-105
Abstract
Recent studies have identified mutations in the complement regulatory gene factor I (CFI) that predispose to atypical hemolytic uremic syndrome (aHUS). CFI is a two-chain serine protease in which the light chain carries the catalytic domain while the heavy chain's function is unclear. It downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (known as cofactor activity). Many CFI mutations in aHUS result in low CFI levels with a consequent quantitative defect in complement regulation. In others, the mutant protein is present in normal amounts but the presumed functional deficiency has not yet been defined. In this report we examine the nature of the... (More)
Recent studies have identified mutations in the complement regulatory gene factor I (CFI) that predispose to atypical hemolytic uremic syndrome (aHUS). CFI is a two-chain serine protease in which the light chain carries the catalytic domain while the heavy chain's function is unclear. It downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (known as cofactor activity). Many CFI mutations in aHUS result in low CFI levels with a consequent quantitative defect in complement regulation. In others, the mutant protein is present in normal amounts but the presumed functional deficiency has not yet been defined. In this report we examine the nature of the functional defect in aHUS-associated CFI mutations. The I322T, D501N and D506V mutations reside in the serine protease domain of CFI and result in secreted proteins that lack C3b and C4b cofactor activity. The delTTCAC (1446-1450) mutant leads to a protein that is not secreted. The R299W mutant lies in a region of the CFI heavy chain of no known function. Our assessments demonstrate decreased C3b and C4b cofactor activity, providing evidence that this region is important for cofactor activity. In two other heavy chain mutants and one probable polymorphic variant, no functional deficiency was identified. These defective mutant proteins will result in an inability to appropriately control the complement cascade at sites of endothelial cell injury. The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS. (Less)
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published
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keywords
Thrombotic thrombocytopenic purpura, Hemolytic uremic syndrome, Complement, Factor I, Factor H, Membrane cofactor protein, Renal transplantation, Cofactor activity
in
Molecular Immunology
volume
45
issue
1
pages
95 - 105
publisher
Pergamon
external identifiers
  • pmid:17597211
  • wos:000250013600011
  • scopus:34548309310
ISSN
1872-9142
DOI
10.1016/j.molimm.2007.05.004
language
English
LU publication?
yes
id
a2eb1619-dbfd-4d5e-982e-6eb3776af088 (old id 1143955)
date added to LUP
2008-08-12 10:35:05
date last changed
2017-08-20 03:54:04
@article{a2eb1619-dbfd-4d5e-982e-6eb3776af088,
  abstract     = {Recent studies have identified mutations in the complement regulatory gene factor I (CFI) that predispose to atypical hemolytic uremic syndrome (aHUS). CFI is a two-chain serine protease in which the light chain carries the catalytic domain while the heavy chain's function is unclear. It downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (known as cofactor activity). Many CFI mutations in aHUS result in low CFI levels with a consequent quantitative defect in complement regulation. In others, the mutant protein is present in normal amounts but the presumed functional deficiency has not yet been defined. In this report we examine the nature of the functional defect in aHUS-associated CFI mutations. The I322T, D501N and D506V mutations reside in the serine protease domain of CFI and result in secreted proteins that lack C3b and C4b cofactor activity. The delTTCAC (1446-1450) mutant leads to a protein that is not secreted. The R299W mutant lies in a region of the CFI heavy chain of no known function. Our assessments demonstrate decreased C3b and C4b cofactor activity, providing evidence that this region is important for cofactor activity. In two other heavy chain mutants and one probable polymorphic variant, no functional deficiency was identified. These defective mutant proteins will result in an inability to appropriately control the complement cascade at sites of endothelial cell injury. The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS.},
  author       = {Kavanagh, David and Richards, Anna and Noris, Marina and Hauhart, Richard and Liszewski, M Kathryn and Karpman, Diana and Goodship, Judith A and Fremeaux-Bacchi, Veronique and Remuzzi, Giuseppe and Goodship, Timothy H J and Atkinson, John P},
  issn         = {1872-9142},
  keyword      = {Thrombotic thrombocytopenic purpura,Hemolytic uremic syndrome,Complement,Factor I,Factor H,Membrane cofactor protein,Renal transplantation,Cofactor activity},
  language     = {eng},
  number       = {1},
  pages        = {95--105},
  publisher    = {Pergamon},
  series       = {Molecular Immunology},
  title        = {Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome},
  url          = {http://dx.doi.org/10.1016/j.molimm.2007.05.004},
  volume       = {45},
  year         = {2008},
}