Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome

Am J Hum Genet. 2001 Feb;68(2):478-84. doi: 10.1086/318201. Epub 2001 Jan 17.


Hemolytic-uremic syndrome (HUS) is a microvasculature disorder leading to microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Most cases of HUS are associated with epidemics of diarrhea caused by verocytotoxin-producing bacteria, but atypical cases of HUS not associated with diarrhea (aHUS) also occur. Early studies describing the association of aHUS with deficiencies of factor H suggested a role for this complement regulator in aHUS. Molecular evidence of factor H involvement in aHUS was first provided by Warwicker et al., who demonstrated that aHUS segregated with the chromosome 1q region containing the factor H gene (HF1) and who identified a mutation in HF1 in a case of familial aHUS with normal levels of factor H. We have performed the mutational screening of the HF1 gene in a novel series of 13 Spanish patients with aHUS who present normal complement profiles and whose plasma levels of factor H are, with one exception, within the normal range. These studies have resulted in the identification of five novel HF1 mutations in four of the patients. Allele HF1 Delta exon2, a genomic deletion of exon 2, produces a null HF1 allele and results in plasma levels of factor H that are 50% of normal. T956M, W1183L, L1189R, and V1197A are missense mutations that alter amino acid residues in the C-terminal portion of factor H, within a region--SCR16-SCR20--that is involved in the binding to solid-phase C3b and to negatively charged cellular structures. This remarkable clustering of mutations in HF1 suggests that a specific dysfunction in the protection of cellular surfaces by factor H is a major pathogenic condition underlying aHUS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Complement Factor H / chemistry
  • Complement Factor H / genetics*
  • Complement Factor H / metabolism
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Hemolytic-Uremic Syndrome / blood
  • Hemolytic-Uremic Syndrome / genetics*
  • Hemolytic-Uremic Syndrome / pathology
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Pedigree


  • CFH protein, human
  • Complement Factor H
  • DNA

Associated data

  • OMIM/235400