Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II)

Kidney Int. 2006 Jul;70(1):42-50. doi: 10.1038/ Epub 2006 Apr 12.


We report a novel pathomechanism for membranoproliferative glomerulonephritis type II (MPGN II) caused by a mutant Factor H protein expressed in the plasma. Genetic analyses of two patients revealed deletion of a single Lys residue (K224) located within the complement regulatory region in domain 4 of Factor H. This deletion resulted in defective complement control: mutant protein purified from the plasma of patients showed severely reduced cofactor and decay-accelerating activity, as well as reduced binding to the central complement component C3b. However, cell-binding activity of the mutant protein was normal and comparable to wild-type Factor H. The patients are daughters of consanguineous parents. As both patients but also their healthy mother were positive for C3 nephritic factor, the mutant Factor H protein is considered relevant for unrestricted activation of the disease-causing activation of the alternative complement pathway. Replacement of functional Factor H by fresh frozen plasma (10-15 ml/kg/14 days) was well tolerated, prevented so far disease progression in both patients, and is in the long run expected to preserve kidney function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Child
  • Complement C3 Nephritic Factor / analysis
  • Complement C3 Nephritic Factor / metabolism
  • Complement Factor H / analysis
  • Complement Factor H / genetics*
  • Complement Factor H / metabolism*
  • Complement Pathway, Alternative*
  • Consanguinity
  • Female
  • Glomerulonephritis, Membranoproliferative / genetics*
  • Glomerulonephritis, Membranoproliferative / immunology*
  • Humans
  • Lysine / chemistry
  • Lysine / genetics
  • Molecular Sequence Data
  • Pedigree
  • Plasma / chemistry
  • Plasma / metabolism
  • Protein Structure, Tertiary / genetics
  • Sequence Deletion


  • Complement C3 Nephritic Factor
  • Complement Factor H
  • Lysine