Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome

Am J Hum Genet. 1999 Dec;65(6):1538-46. doi: 10.1086/302673.


Atypical hemolytic uremic syndrome (HUS) presents with the clinical features of hypertension, microangiopathic hemolytic anemia, and acute renal failure. Both dominant and recessive modes of inheritance have been reported. This study describes the genetic and functional analysis of a large Bedouin kindred with autosomal recessive HUS. The kindred consists of several related nuclear families in which all parent unions of affected children are consanguineous. A previous report demonstrated that a dominant form of HUS maps to chromosome 1q and that complement factor H (CFH), a regulatory component of the complement system, lies within the region and is involved in the dominant disorder. Early-onset and persistent hypocomplementemia in this Bedouin kindred prompted us to evaluate the CFH gene. Linkage analysis was performed, demonstrating linkage between the disorder and the markers near the CFH gene. Mutation analysis of the CFH coding region revealed a single missense mutation. Functional analyses demonstrate that the mutant CFH is properly expressed and synthesized but that it is not transported normally from the cell. This is the first study reporting that a recessive, atypical, early-onset, and relapsing HUS is associated with the CFH protein and that a CFH mutation affects intracellular trafficking and secretion.

MeSH terms

  • Age of Onset
  • Base Sequence
  • Cells, Cultured
  • Chromosomes, Human, Pair 1 / genetics
  • Complement C3 / analysis
  • Complement C3 / biosynthesis
  • Complement C3 / metabolism
  • Complement Factor H / analysis
  • Complement Factor H / biosynthesis
  • Complement Factor H / genetics*
  • Complement Factor H / metabolism
  • Consanguinity
  • Exons / genetics
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Genes, Recessive / genetics*
  • Genetic Linkage / genetics*
  • Genetic Markers / genetics
  • Hemolytic-Uremic Syndrome / blood
  • Hemolytic-Uremic Syndrome / genetics*
  • Hemolytic-Uremic Syndrome / pathology
  • Humans
  • Infant, Newborn
  • Male
  • Mutation / genetics*
  • Pedigree
  • Polymorphism, Single-Stranded Conformational
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin


  • CFH protein, human
  • Complement C3
  • Genetic Markers
  • RNA, Messenger
  • Complement Factor H