title: Familial haemolytic uraemic syndrome and an MCP mutation.
abstract: BACKGROUND
  Mutations in factor H (HF1) have been reported in a consistent number of diarrhoea-negative, non-Shiga toxin-associated cases of haemolytic uraemic syndrome (D-HUS). However, most patients with D-HUS have no HF1 mutations, despite decreased serum concentrations of C3. Our aim, therefore, was to assess whether genetic abnormalities in other complement regulatory proteins are involved.
  
  
  METHODS
  We screened genes that encode the complement regulatory proteins-ie, factor H related 5, complement receptor 1, and membrane cofactor protein (MCP)-by PCR-single-strand conformation polymorphism (PCR-SSCP) and by direct sequencing, in 25 consecutive patients with D-HUS, an abnormal complement profile, and no HF1 mutation, from our International Registry of Recurrent and Familial HUS/TTP (HUS/thrombotic thrombocytopenic purpura).
  
  
  RESULTS
  We identified a heterozygous mutation in MCP, a surface-bound complement regulator, in two patients with a familial history of HUS. The mutation causes a change in three aminoacids at position 233-35 and insertion of a premature stop-codon, which results in loss of the transmembrane domain of the protein and severely reduced cell-surface expression of MCP.
  
  
  CONCLUSIONS
  Results of previous studies on HF1 indicate an association between HF1 deficiency and D-HUS. Our findings of an MCP mutation in two related patients suggest that impaired regulation of complement activation might be a factor in the pathogenesis of genetic forms of HUS. MCP could be a second putative candidate gene for D-HUS. The protein is highly expressed in the kidney and plays a major part in regulation of glomerular C3 activation. We propose, therefore, that reduced expression of MCP in response to complement-activating stimuli could prevent restriction of complement deposition on glomerular endothelial cells, leading to microvascular cell damage and tissue injury.
authors: Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Villa Camozzi-Ranica, Bergamo, Italy. noris@marionegri.it
authors: Marina
authors: M
authors: Noris
authors: Simona
authors: S
authors: Brioschi
authors: Jessica
authors: J
authors: Caprioli
authors: Marta
authors: M
authors: Todeschini
authors: Elena
authors: E
authors: Bresin
authors: Francesca
authors: F
authors: Porrati
authors: Sara
authors: S
authors: Gamba
authors: Giuseppe
authors: G
authors: Remuzzi
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015703:Antigens, CD / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D003169:Complement Inactivator Proteins / Q000235:genetics*; D003165:Complement System Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007678:Kidney Glomerulus / Q000503:physiopathology; D008297:Male; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational; D011951:Receptors, Complement / Q000235:genetics
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; C493495:CFH protein, human; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D017242:Complement Factor H; D003165:Complement System Proteins