title: Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
abstract: BACKGROUND
  Complement is a key component of the innate immune system, and variation in genes that regulate its activation is associated with renal and other disease. We aimed to establish the genetic basis for a familial disorder of complement regulation associated with persistent microscopic haematuria, recurrent macroscopic haematuria, glomerulonephritis, and progressive renal failure.
  
  
  METHODS
  We sought patients from the West London Renal and Transplant Centre (London, UK) with unusual renal disease and affected family members as a method of identification of new genetic causes of kidney disease. Two families of Cypriot origin were identified in which renal disease was consistent with autosomal dominant transmission and renal biopsy of at least one individual showed C3 glomerulonephritis. A mutation was identified via a genome-wide linkage study and candidate gene analysis. A PCR-based diagnostic test was then developed and used to screen for the mutation in population-based samples and in individuals and families with renal disease.
  
  
  RESULTS
  Occurrence of familial renal disease cosegregated with the same mutation in the complement factor H-related protein 5 gene (CFHR5). In a cohort of 84 Cypriots with unexplained renal disease, four had mutation in CFHR5. Overall, we identified 26 individuals with the mutation and evidence of renal disease from 11 ostensibly unrelated kindreds, including the original two families. A mutant CFHR5 protein present in patient serum had reduced affinity for surface-bound complement. We term this renal disease CFHR5 nephropathy.
  
  
  CONCLUSIONS
  CFHR5 nephropathy accounts for a substantial burden of renal disease in patients of Cypriot origin and can be diagnosed with a specific molecular test. The high risk of progressive renal disease in carriers of the CFHR5 mutation implies that isolated microscopic haematuria or recurrent macroscopic haematuria should not be regarded as a benign finding in individuals of Cypriot descent.
  
  
  BACKGROUND
  UK Medical Research Council and Wellcome Trust.
authors.affiliation: Division of Medicine, University College, London, UK.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gale
authors.forename: Elena Goicoechea
authors.initials: EG
authors.lastname: de Jorge
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Rubén
authors.initials: R
authors.lastname: Martinez-Barricarte
authors.forename: Andreas
authors.initials: A
authors.lastname: Hadjisavvas
authors.forename: Adam G
authors.initials: AG
authors.lastname: McLean
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.forename: Alkis
authors.initials: A
authors.lastname: Pierides
authors.forename: Kyriacos
authors.initials: K
authors.lastname: Kyriacou
authors.forename: Yiannis
authors.initials: Y
authors.lastname: Athanasiou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Voskarides
authors.forename: Constantinos
authors.initials: C
authors.lastname: Deltas
authors.forename: Andrew
authors.initials: A
authors.lastname: Palmer
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Santiago Rodriguez
authors.initials: SR
authors.lastname: de Cordoba
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
mesh_terms: D000328:Adult; D000368:Aged; D001798:Blood Proteins / Q000235:genetics*; D003182:Complement C5 / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics*; D003165:Complement System Proteins; D003535:Cyprus / Q000453:epidemiology / Q000208:ethnology; D019353:Endemic Diseases; D005260:Female; D055106:Genome-Wide Association Study; D005921:Glomerulonephritis / Q000097:blood / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D001798:Blood Proteins; C432223:CFHR5 protein, human; D003182:Complement C5; D017242:Complement Factor H; D003165:Complement System Proteins
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