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Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding

Elena Volokhina1, Dineke Westra, Xiaoguang Xue

  • 1Department of Pediatric Nephrology (804), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Pediatric Nephrology (Berlin, Germany)
|June 7, 2012
PubMed

Insights

A novel C3 gene mutation (p.Lys65Gln) was identified in atypical hemolytic uremic syndrome (aHUS) patients, leading to reduced C3b binding to factor H. This finding may help predict aHUS recurrence post-kidney transplant.

Area of Science:

  • Complement system genetics
  • Nephrology
  • Rare disease research

Background:

  • Atypical hemolytic uremic syndrome (aHUS) involves complement system dysregulation, often leading to kidney failure.
  • Genetic factors and autoantibodies against complement factor H (CFH) are implicated in aHUS.
  • Prognostic DNA analysis of risk genes is crucial for managing aHUS recurrence after renal transplantation.

Purpose of the Study:

  • To investigate the role of mutations in the C3 gene, encoding a central complement component, in aHUS patients.
  • To analyze the functional impact of identified C3 mutations on complement factor H (CFH) binding.

Main Methods:

  • Sanger sequencing was used to screen the C3 gene in 70 aHUS patients.
  • Recombinant C3b proteins (mutated and wild type) were produced.
  • Enzyme-linked immunosorbent assay (ELISA) was employed to analyze the binding affinity of C3b to CFH.

Main Results:

  • A novel missense mutation, p.Lys65Gln in C3, was identified in three adult aHUS patients.
  • This mutation resulted in decreased binding of C3b to CFH in vitro.
  • All affected patients experienced aHUS after kidney transplantation or disease recurrence post-transplant.

Conclusions:

  • The identified C3 p.Lys65Gln mutation impairs C3b binding to CFH, potentially disrupting C3b inactivation.
  • This mutation is likely associated with aHUS development or recurrence following kidney transplantation.
  • The p.Lys65Gln C3 variant may serve as a significant prognostic marker for aHUS post-transplant.
Abstract

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