Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome

Blood. 2010 Jan 14;115(2):379-87. doi: 10.1182/blood-2009-05-221549. Epub 2009 Oct 27.

Abstract

Factor H autoantibodies have been reported in approximately 10% of patients with atypical hemolytic uremic syndrome (aHUS) and are associated with deficiency of factor H-related proteins 1 and 3. In this study we examined the prevalence of factor H autoantibodies in the Newcastle cohort of aHUS patients, determined whether the presence of such autoantibodies is always associated with deficiency of factor H-related proteins 1 and 3, and examined whether such patients have additional susceptibility factors and/or mutations in the genes encoding complement regulator/activators. We screened 142 patients with aHUS and found factor H autoantibodies in 13 individuals (age 1-11 years). The presence of the autoantibodies was confirmed by Western blotting. By using multiplex ligation-dependent probe amplification we measured complement factor H-related (CFHR)1 and CFHR3 copy number. In 10 of the 13 patients there were 0 copies of CFHR1, and in 3 patients there were 2. In 3 of the patients with 0 copies of CFHR1 there was 1 copy of CFHR3, and these individuals exhibited a novel deletion incorporating CFHR1 and CFHR4. In 5 patients mutations were identified: 1 in CFH, 1 in CFI, 1 in CD46, and 2 in C3. The latter observation emphasizes that multiple concurrent factors may be necessary in individual patients for disease manifestation.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoproteins / genetics*
  • Apolipoproteins / immunology
  • Apolipoproteins / metabolism
  • Autoantibodies / blood*
  • Autoantibodies / immunology
  • Blood Proteins / genetics*
  • Blood Proteins / immunology
  • Blood Proteins / metabolism
  • Child
  • Child, Preschool
  • Cohort Studies
  • Complement C3 / genetics*
  • Complement C3 / immunology
  • Complement C3 / metabolism
  • Complement C3b Inactivator Proteins / genetics*
  • Complement C3b Inactivator Proteins / immunology
  • Complement C3b Inactivator Proteins / metabolism
  • Complement Factor H / genetics*
  • Complement Factor H / immunology
  • Complement Factor H / metabolism
  • Complement Factor I / genetics*
  • Complement Factor I / immunology
  • Complement Factor I / metabolism
  • Female
  • Gene Dosage
  • Hemolytic-Uremic Syndrome / blood*
  • Hemolytic-Uremic Syndrome / genetics*
  • Hemolytic-Uremic Syndrome / immunology
  • Humans
  • Infant
  • Male
  • Membrane Cofactor Protein / genetics*
  • Membrane Cofactor Protein / immunology
  • Membrane Cofactor Protein / metabolism
  • Sequence Deletion

Substances

  • Apolipoproteins
  • Autoantibodies
  • Blood Proteins
  • CD46 protein, human
  • CFHR1 protein, human
  • CFHR3 protein, human
  • CFHR4 protein, human
  • Complement C3
  • Complement C3b Inactivator Proteins
  • Membrane Cofactor Protein
  • Complement Factor H
  • CFI protein, human
  • Complement Factor I