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Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or

Sara C Nilsson1, Nikolina Kalchishkova, Leendert A Trouw

  • 1Department of Laboratory Medicine, Medical Protein Chemistry, Malmö University Hospital, Lund University, Sweden.

European Journal of Immunology
|October 31, 2009
PubMed

Insights

Mutations in complement factor I (FI) impact its secretion and function, disrupting complement system regulation. This dysfunction is linked to atypical hemolytic uremic syndrome (aHUS), highlighting FI's critical role.

Area of Science:

  • Immunology
  • Molecular Biology
  • Genetics

Background:

  • The complement system is crucial for innate immunity and is tightly regulated by inhibitors like factor I (FI).
  • Defects in FI and its cofactors are implicated in the pathogenesis of atypical hemolytic uremic syndrome (aHUS).

Purpose of the Study:

  • To investigate the impact of complement factor I (FI) mutations associated with aHUS on FI secretion and function.
  • To elucidate the molecular mechanisms by which FI mutations contribute to aHUS pathogenesis.

Main Methods:

  • Analysis of 14 heterozygous FI mutations (premature stop codons or amino acid substitutions) found in aHUS patients.
  • Expression and secretion studies using human embryonic kidney 293 cells.
  • Functional assays to assess the degradation of complement factors C4b and C3b by purified FI mutants in fluid-phase and on endothelial cells.

Main Results:

  • Most FI mutants were expressed but showed impaired secretion, with many retained in the early secretory pathway.
  • Five of six purified secreted FI mutants exhibited altered degradation of C4b/C3b.
  • Specific mutants displayed reduced cleavage of surface-bound C3b, and the D501N mutant was severely impaired in both solution and cell-based assays.

Conclusions:

  • Mutations in complement factor I significantly affect both the secretion and enzymatic function of FI.
  • Impaired FI secretion and function lead to dysregulation of the complement system, contributing to the development of aHUS.

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