Characterization of a factor H mutation that perturbs the alternative pathway of complement in a family with membranoproliferative GN

Edwin K S Wong, Holly E Anderson, Andrew P Herbert, Rachel C Challis, Paul Brown, Geisilaine S Reis, James O Tellez, Lisa Strain, Nicholas Fluck, Ann Humphrey, Alison Macleod, Anna Richards, Daniel Ahlert, Mauro Santibanez-Koref, Paul N Barlow, Kevin J Marchbank, Claire L Harris, Timothy H J Goodship, David Kavanagh

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.

Original languageEnglish
Pages (from-to)2425-33
Number of pages9
JournalJournal of the American Society of Nephrology
Issue number11
Publication statusPublished - Nov 2014

Keywords / Materials (for Non-textual outputs)

  • animals
  • Complement Factor H
  • Complement Pathway
  • Crystallography
  • Erythrocytes
  • family health
  • female
  • Glomerulonephritis, Membranoproliferative
  • Haplotypes
  • Heterozygote
  • humans
  • kidney diseases
  • male
  • pedigree
  • Tertiary
  • Protein Structure
  • sheep
  • Structure-Activity Relationship
  • polymorphism
  • X-Ray
  • alternative


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