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

David Kavanagh, Anna Richards, Marina Noris, Richard Hauhart, M. Kathryn Liszewski, Diana Karpman, Judith A. Goodship, Veronique Fremeaux-Bacchi, Giuseppe Remuzzi, Timothy H J Goodship, John P. Atkinson

Research output: Contribution to journalArticlepeer-review

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 α′ 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.

Original languageEnglish
Pages (from-to)95-105
Number of pages11
JournalMolecular Immunology
Volume45
Issue number1
DOIs
Publication statusPublished - Jan 2008

Keywords

  • Cofactor activity
  • Complement
  • Factor H
  • Factor I
  • Hemolytic uremic syndrome
  • Membrane cofactor protein
  • Renal transplantation
  • Thrombotic thrombocytopenic purpura

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

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